February 20, 2024

Those of us with a friend who can eat sugary items every day and not gain an ounce or a relative who developed heart disease despite shunning saturated fats know that one-size-fits-all dietary recommendations do not reflect how differently we respond to food. But now one of the most inclusive and ambitious new studies of diets could change that, yielding insights that will allow experts to finally tailor their recommendations for different people.

Beginning this spring, 13 sites across the United States will begin enrolling 10,000 people spanning a wide variety of ages and weights to better determine the important factors involved in what is called precision nutrition. Specific efforts will be made to include those often overlooked in nutrition science: seniors over 65, people of color, rural residents, people with disabilities, and sexual minorities.

During the first phase of the research, which will last two weeks, everyone will be instructed to eat as they typically do. In phase two, 1,500 people will be assigned one of several diets with meals sent directly to their homes. And in the final phase, 500 people chosen from the larger group will eat while residing in a research center for two weeks. The latter is a large number for a controlled nutritional study, which typically involves just few dozen participants, says Holly Nicastro, who will coordinate this $170 million National Institutes of Health research program called Nutrition for Precision Health. Participants will be selected from the NIH’s All of Us health research program, which anyone can join.

This large and diverse effort will “get us one step closer to be able to provide more granular nutrition recommendations for groups of individuals,” says Sai Krupa Das, a metabolism scientist at Tufts University, one of six research centers coordinating the enrollment sites.

How the study will work

During the study, researchers will regularly conduct urine and blood tests and complete a census of each person’s gut microbiome—the trillions of organisms that permanently reside in the digestive tract. The participants will wear glucose monitors to record rising and falling levels of blood sugars—a marker of how well the body processes carbohydrates and an important indicator of health. Daily behaviors like sleep, stress, and the times people eat, among other factors, will also be tracked.

The new study will change our understanding of human diets because it is radically different from how most nutrition studies are conducted, says Diana Thomas, professor of mathematics at the U.S. Military Academy at West Point, who is involved in the research. Nutrition scientists generally examine a single food item in a homogenous population, inquiring, say, whether blueberries reduce the risk of cardiovascular disease in Americans (the answer to that is still unclear). In this study we are not beginning with a hypothesis, she says, but rather “we’re asking, what are the factors involved?”

The goal is to tease out the many variables that impact nutritional responses and develop algorithms that predict them, allowing nutritionists to offer dietary advice to others with similar characteristics.

Offering more targeted recommendations is crucial for improving public health, Das says. The current approach has led many people to tune out expert dietary advice, whether because the advice seems to frequently change (the classic: eggs are bad; eggs are good) or because they tried a recommended way of eating and found it wasn’t ideal for them. “Precision nutrition will allow us to do better than the one-size-fits all, go-eat-the-Mediterranean-diet advice. Instead, we’d say, ‘If you have certain ethnicities, characteristics, physical responses to foods, this diet may be more suitable.’ That’s the step we’re getting closer to,” she says.

Das cautions that new advice derived from the research will not reach the level of the individual, which is why experts prefer the term precision nutrition to another widely used term, personalized nutrition.

The study will focus on eating for optimal health rather than for losing weight, but the two go hand in hand, Das says. “We are not providing calorie-restricted diets, but I think the response in terms of trying to optimize metabolism would help for weight management as well.”

Genes vs. the microbiome

Several decades of research have already yielded clues about which elements mold overall health.

One of these is genetics. This field was previously called nutrigenomics, but that fell out of favor when it became apparent that genes play a less prominent role in how the body responds to food than initially thought, says José Ordovás, director of nutrition and genomics at Tufts University.

In a small number of cases, scientists have tied a specific gene to a direct health effect. The gene CYP1A2, for example, is almost single-handedly responsible for determining how quickly enzymes metabolize caffeine in the liver. Genetic variations determine whether an evening cup of joe keeps a person up all night or still allows them to get a restful night’s sleep. It also influences whether the coffee will help a person work out at higher intensity, such as riding a bike faster.

“Genetics are involved, but it will not give us the predictive equations to individualize recommendations, because so many other factors are involved,” Ordovás says. Since many of those factors, especially behavior, are easier to change than our genes, understanding them should lead to a more effective approach to improving health, he says.

Hundreds of studies have shown that the microbiome—the bacteria, fungi, parasites, and viruses that reside in the gut—is a critical factor in how the body processes food. Consuming artificial sweeteners, for example, alters the composition and function of the microbiome in a way that increases glucose intolerance in healthy people. And certain intestinal microbes persist in obese mice after dieting, which predispose them—and presumably us—to regain the weight. 

There’s still much to learn about the microbiome, including its optimal composition, how the microbes work synergistically and how lifestyle impacts this community, says Eran Elinav, head of systems immunology at Israel’s Weizmann Institute of Science and a prolific microbiome researcher.

How lifestyle influences how we process food

One of the trickiest things about figuring out the perfect diet for each person is the complex interplay between our genome, microbiome, and lifestyle factors—the latter of which scientists call the exposome.

One of those lifestyle factors is the time we eat dinner, Elinav says. His lab determined that the gut microbiome adheres to a circadian rhythm, with the composition of the microbiota predictably changing their numbers and function during a 24-hour period. They do this by responding to signals from sleeping and eating behaviors.

“When we disturb our sleep-wake patterns with shift work or jet lag,” Elinav says, “one of the first things that happens is this disrupts the diurnal activity of the microbes.” The increased rates of obesity, type 2 diabetes, and cancers associated with people whose sleep and eating schedule is chronically disrupted stem from this alteration in the microbiome, studies in mice suggest.

Poor sleep, along with intense stress, additionally disrupts metabolism and has other negative health effects even in people eating a healthy diet, Tufts’ Das says.

The NIH’s precision nutrition research will be the most comprehensive effort to use genes, microbiota, and the exposome to understand and predict nutritional responses to foods, but it won’t be the first. Several earlier studies have paved the way.

One effort, led by Elinav’s lab and published in the journal Cell in 2015, involved feeding identical meals to 800 people and continuously monitoring their blood glucose levels. The week-long study revealed that glucose responses among the participants varied significantly after each meal. Researchers noted that the composition of their microbiome played a key role in determining that response, but other factors were inevitably involved.

A few years later a large study in the United Kingdom sought to expand knowledge of the variables at play. Called the Personalized Responses to Dietary Composition Trial, or PREDICT, the research involved a thousand adults—including some genetically identical twins— whose gut microbiota, blood fats, glucose levels following meals, inflammation, and other factors were monitored for two weeks. Tracking blood glucose throughout the day was again an important element, says Tufts’ Ordovás, one of the coauthors. Such continuous monitoring enabled researchers to measure the effects of specific foods.

Here too, wide variations appeared indicating that the participants’ bodies were processing the same nutrients differently. Genetic factors proved to have a modest impact, but the findings showed how complicated the digestive system is. Certain gut microbes—including Prevotella copri and Blastocystis—were more important than genes for processing some foods—but both still accounted for only a small part of the overall differences.

The goal of the upcoming NIH research is to improve the understanding of factors that account for those differences. The hope is this will enable people to adjust their lifestyle and diet and perhaps their gut microbes to improve their body’s responses to various nutrients. (Whether manipulating the microbiota, such as through dietary changes, has a lasting impact is still unclear.)

For now, Das says the best nutritional advice she and others offer stick to the basics: fill your plate with fiber-rich vegetables and fruits and shun highly processed fare in favor of whole foods.

“In the next five to 10 years there will be huge changes in how we look at diets,” West Point’s Thomas predicts. “Once results from the NIH study begin to appear, we’re just going to know so much more.”


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