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Targeting the Microbiome to Treat Malnutrition

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Caption: A Bangladeshi mother and child in the Nutritional Rehabilitation Unit.
Credit: International Centre for Diarrhoeal Disease Research, Bangladesh

A few years ago, researchers discovered that abnormalities in microbial communities, or microbiomes, in the intestine appear to contribute to childhood malnutrition. Now comes word that this discovery is being translated into action, with a new study showing that foods formulated to repair the “gut microbiome” may help malnourished kids rebuild their health [1].

In a month-long clinical trial in Bangladesh, 63 children received either regular foods to treat malnutrition or alternative formulations for needed calories and nutrition that also encouraged growth of beneficial microbes in the intestines. The kids who ate the microbiome-friendly diets showed improvements in their microbiome, which helps to extract and metabolize nutrients in our food to help the body grow. They also had significant improvements in key blood proteins associated with bone growth, brain development, immunity, and metabolism; those who ate standard therapeutic food did not experience the same benefit.

Globally, malnutrition affects an estimated 238 million children under the age 5, stunting their normal growth, compromising their health, and limiting their mental development [2]. Malnutrition can arise not only from a shortage of food but from dietary imbalances that don’t satisfy the body’s need for essential nutrients. Far too often, especially in impoverished areas, the condition can turn extremely severe and deadly. And the long term effects on intellectual development can limit the ability of a country’s citizens to lift themselves out of poverty.

Jeffrey Gordon, Washington University School of Medicine in St. Louis, and his NIH-supported research team have spent decades studying what constitutes a normal microbiome and how changes can affect health and disease. Their seminal studies have revealed that severely malnourished kids have “immature” microbiomes that don’t develop in the intestine like the microbial communities seen in well nourished, healthy children of the same age.

Gordon and team have also found that this microbial immaturity doesn’t resolve when kids consume the usual supplemental foods [3]. In another study, they turned to mice raised under sterile conditions and with no microbes of their own to demonstrate this cause and effect. The researchers colonized the intestines of the germ-free mice with microbes from malnourished children, and the rodents developed similar abnormalities in weight gain, bone growth, and metabolism [4].

All of this evidence raised a vital question: Could the right combination of foods “mature” the microbiome and help to steer malnourished children toward a healthier state?

To get the answer, Gordon and his colleagues at the International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh, led by Tahmeed Ahmed, first had to formulate the right, microbiome-friendly food supplements, and that led to some interesting science. They carefully characterized over time the immature microbiomes found in Bangladeshi children treated for severe malnutrition. This allowed them to test their new method for analyzing how individual microbial species fluctuate over time and in relationship to one another in the intestine [5]. The team then paired up these data with measurements of a set of more than 1,300 blood proteins from the children that provide “readouts” of their biological state.

Their investigation identified a network of 15 bacterial species that consistently interact in the gut microbiomes of Bangladeshi children. This network became their means to characterize sensitively and accurately the development of a child’s microbiome and/or its relative state of repair.

Next, they turned to mice colonized with the same collections of microbes found in the intestines of the Bangladeshi children. Gordon’s team then tinkered with the animals’ diets in search of ingredients commonly consumed by young children in Bangladesh that also appeared to encourage a healthier, more mature microbiome. They did similar studies in young pigs, whose digestive and immune systems more closely resemble humans.

The Gordon team settled on three candidate microbiome-friendly formulations. Two included chickpea flour, soy flour, peanut flour, and banana at different concentrations; one of these two also included milk powder. The third combined chickpea flour and soy flour. All three contained similar amounts of protein, fat, and calories.

The researchers then launched a randomized, controlled clinical trial with children from a year to 18 months old with moderate acute malnutrition. These young children were enrolled into one of four treatment groups, each including 14 to 17 kids. Three groups received one of the newly formulated foods. The fourth group received standard rice-and-lentil-based meals.

The children received these supplemental meals twice a day for four weeks at the International Centre for Diarrhoeal Disease Research followed by two-weeks of observation. Mothers were encouraged throughout the study to continue breastfeeding their children.

The formulation containing chickpea, soy, peanut, and banana, but no milk powder, stood out above the rest in the study. Children taking this supplement showed a dramatic shift toward a healthier state as measured by those more than 1,300 blood proteins. Their gut microbiomes also resembled those of healthy children their age.

Their new findings published in the journal Science offer the first evidence that a therapeutic food, developed to support the growth and development of a healthy microbiome, might come with added benefits for children suffering from malnutrition. Importantly, the researchers took great care to design the supplements with foods that are readily available, affordable, culturally acceptable, and palatable for young children in Bangladesh.

A month isn’t nearly long enough to see how the new foods would help children grow and recover over time. So, the researchers are now conducting a much larger study of their leading supplement in children with histories of malnutrition, to explore its longer-term health effects for them and their microbiomes. The hope is that these new foods and others adapted for use around the world soon will help many more kids grow up to be healthy adults.

References:

[1] Effects of microbiota-directed foods in gnotobiotic animals and undernourished children. Gehrig JL, Venkatesh S, Chang HW, Hibberd MC, Kung VL, Cheng J, Chen RY, Subramanian S, Cowardin CA, Meier MF, O’Donnell D, Talcott M, Spears LD, Semenkovich CF, Henrissat B, Giannone RJ, Hettich RL, Ilkayeva O, Muehlbauer M, Newgard CB, Sawyer C, Head RD, Rodionov DA, Arzamasov AA, Leyn SA, Osterman AL, Hossain MI, Islam M, Choudhury N, Sarker SA, Huq S, Mahmud I, Mostafa I, Mahfuz M, Barratt MJ, Ahmed T, Gordon JI. Science. 2019 Jul 12;365(6449).

[2] Childhood Malnutrition. World Health Organization

[3] Persistent gut microbiota immaturity in malnourished Bangladeshi children. Subramanian S, Huq S, Yatsunenko T, Haque R, Mahfuz M, Alam MA, Benezra A, DeStefano J, Meier MF, Muegge BD, Barratt MJ, VanArendonk LG, Zhang Q, Province MA, Petri WA Jr, Ahmed T, Gordon JI. Nature. 2014 Jun 19;510(7505):417-21.

[4] Gut bacteria that prevent growth impairments transmitted by microbiota from malnourished children. Blanton LV, Charbonneau MR, Salih T, Barratt MJ, Venkatesh S, Ilkaveya O, Subramanian S, Manary MJ, Trehan I, Jorgensen JM, Fan YM, Henrissat B, Leyn SA, Rodionov DA, Osterman AL, Maleta KM, Newgard CB, Ashorn P, Dewey KG, Gordon JI. Science. 2016 Feb 19;351(6275).

[5] A sparse covarying unit that describes healthy and impaired human gut microbiota development. Raman AS, Gehrig JL, Venkatesh S, Chang HW, Hibberd MC, Subramanian S, Kang G, Bessong PO, Lima AAM, Kosek MN, Petri WA Jr, Rodionov DA, Arzamasov AA, Leyn SA, Osterman AL, Huq S, Mostafa I, Islam M, Mahfuz M, Haque R, Ahmed T, Barratt MJ, Gordon JI. Science. 2019 Jul 12;365(6449).

Links:

Childhood Nutrition Facts (Centers for Disease Control and Prevention)

Gordon Lab (Washington University School of Medicine in St. Louis)

NIH Human Microbiome Project

International Centre for Diarrhoeal Disease Research (Dhaka, Bangladesh)

NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of General Medical Sciences; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Center for Advancing Translational Sciences; National Cancer Institute


Study Finds No Benefit for Dietary Supplements

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Eating healthy
Credit: iStock/Artfully79

More than half of U.S. adults take dietary supplements [1]. I don’t, but some of my family members do. But does popping all of these vitamins, minerals, and other substances really lead to a longer, healthier life? A new nationwide study suggests it doesn’t.

Based on an analysis of survey data gathered from more than 27,000 people over a six-year period, the NIH-funded study found that individuals who reported taking dietary supplements had about the same risk of dying as those who got their nutrients through food. What’s more, the mortality benefits associated with adequate intake of vitamin A, vitamin K, magnesium, zinc, and copper were limited to food consumption.

The study, published in the Annals of Internal Medicine, also uncovered some evidence suggesting that certain supplements might even be harmful to health when taken in excess [2]. For instance, people who took more than 1,000 milligrams of supplemental calcium per day were more likely to die of cancer than those who didn’t.

The researchers, led by Fang Fang Zhang, Tufts University, Boston, were intrigued that so many people take dietary supplements, despite questions about their health benefits. While the overall evidence had suggested no benefits or harms, results of a limited number of studies had suggested that high doses of certain supplements could be harmful in some cases.

To take a broader look, Zhang’s team took advantage of survey data from tens of thousands of U.S. adults, age 20 or older, who had participated in six annual cycles of the National Health and Nutrition Examination Survey (NHANES) between 1999-2000 and 2009-2010. NHANES participants were asked whether they’d used any dietary supplements in the previous 30 days. Those who answered yes were then asked to provide further details on the specific product(s) and how long and often they’d taken them.

Just over half of participants reported use of dietary supplements in the previous 30 days. Nearly 40 percent reported use of multivitamins containing three or more vitamins.

Nutrient intake from foods was also assessed. Each year, the study’s participants were asked to recall what they’d eaten over the last 24 hours. The researchers then used that information to calculate participants’ nutrient intake from food. Those calculations indicated that more than half of the study’s participants had inadequate intake of vitamins D, E, and K, as well as choline and potassium.

Over the course of the study, more than 3,600 of the study’s participants died. Those deaths included 945 attributed to cardiovascular disease and 805 attributed to cancer. The next step was to look for any association between the nutrient intake and the mortality data.

The researchers found the use of dietary supplements had no influence on mortality. People with adequate intake of vitamin A, vitamin K, magnesium, zinc, and copper were less likely to die. However, that relationship only held for nutrient intake from food consumption.

People who reported taking more than 1,000 milligrams of calcium per day were more likely to die of cancer. There was also evidence that people who took supplemental vitamin D at a dose exceeding 10 micrograms (400 IU) per day without a vitamin D deficiency were more likely to die from cancer.

It’s worth noting that the researchers did initially see an association between the use of dietary supplements and a lower risk of death due to all causes. However, those associations vanished when they accounted for other potentially confounding factors.

For example, study participants who reported taking dietary supplements generally had a higher level of education and income. They also tended to enjoy a healthier lifestyle. They ate more nutritious food, were less likely to smoke or drink alcohol, and exercised more. So, it appears that people who take dietary supplements are likely to live a longer and healthier life for reasons that are unrelated to their supplement use.

While the study has some limitations, including the difficulty in distinguishing association from causation, and a reliance on self-reported data, its findings suggest that the regular use of dietary supplements should not be recommended for the general U.S. population. Of course, this doesn’t rule out the possibility that certain subgroups of people, including perhaps those following certain special diets or with known nutritional deficiencies, may benefit.

These findings serve up a reminder that dietary supplements are no substitute for other evidence-based approaches to health maintenance and eating nutritious food. Right now, the best way to live a long and healthy life is to follow the good advice offered by the rigorous and highly objective reviews provided by the U.S. Preventive Services Task Force [3]. Those tend to align with what I hope your parents offered: eat a balanced diet, including plenty of fruits, veggies, and healthy sources of calcium and protein. Don’t smoke. Use alcohol in moderation. Avoid recreational drugs. Get plenty of exercise.

References:

[1] Trends in Dietary Supplement Use Among US Adults From 1999-2012. Kantor ED, Rehm CD, Du M, White E, Giovannucci EL. JAMA. 2016 Oct 11;316(14):1464-1474.

[2] Association among dietary supplement use, nutrient intake, and mortality among U.S. adults. Chen F, Du M, Blumberg JB, Ho Chui KK, Ruan M, Rogers G, Shan Z, Zeng L, Zhang. Ann Intern Med. 2019 Apr 9. [Epub ahead of print].

[3] Vitamin Supplementation to Prevent Cancer and CVD: Preventive Medication. U.S. Preventive Services Task Force, February 2014.

Links:

Office of Dietary Supplements (NIH)

Healthy Eating Plan (National Heart, Lung, and Blood Institute/NIH)

National Health and Nutrition Examination Survey (Centers for Disease Control and Prevention, Atlanta)

U.S. Preventive Services Task Force (Rockville, MD)

Fang Fang Zhang (Tufts University, Boston)

NIH Support: National Institute on Minority Health and Health Disparities


Are Sports Organizations Playing a Role in America’s Obesity Problem?

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Sports SponsorsLast September, the National Football League struck a deal with Frito-Lay that allowed the company to produce limited-edition bags of Tostitos tortilla chips, with each package bearing the logo of one of 19 featured NFL teams. Several months earlier, Major League Baseball announced that Nathan’s Famous would be its first-ever official hot dog. Now the first-ever comprehensive analysis of such food and beverage sponsorships by major sports organizations shows just how pervasive these deals are. The confusing messages they send about physical fitness and healthy eating habits can’t be helping our national problem with obesity [1].

Among the 10 sports organizations that young viewers watch most, from the NFL to Little League, the NIH-funded research team identified dozens of sponsors and hundreds of associated advertisements promoting food and beverage products. The vast majority of those ads touted unhealthy items, including chips, candies, sodas, and other foods high in fat, sodium, or sugar, and low in nutritional value.

Those findings are especially concerning in light of the latest figures from the National Health and Nutrition Examination Survey (NHANES), co-supported by NIH [2], It shows that, despite long-standing public health efforts to curb the obesity epidemic, more than 18 percent of young people in America remain obese. Among adults, the picture is even more discouraging: nearly 40 percent of American adults were obese in 2015-2016, up from about 34 percent in 2007-2008.


Creative Minds: The Worm Tissue-ome Teaches Developmental Biology for Us All

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C. elegans

Caption: An adult Caenorhabditis elegans, 5 days
Credit: Coleen Murphy, Princeton University, Princeton, NJ

In the nearly 40 years since Nobel Prize-winning scientist Sydney Brenner proposed using a tiny, transparent soil worm called Caenorhabditis elegans as a model organism for biomedical research, C. elegans has become one of the most-studied organisms on the planet. Researchers have determined that C. elegans has exactly 959 cells, 302 of which are neurons. They have sequenced and annotated its genome, developed an impressive array of tools to study its DNA, and characterized the development of many of its tissues.

But what researchers still don’t know is exactly how all of these parts work together to coordinate this little worm’s response to changes in nutrition, environment, health status, and even the aging process. To learn more, 2015 NIH Director’s Pioneer Award winner Coleen Murphy of Princeton University, Princeton, NJ, has set out to analyze which genes are active, or transcribed, in each of the major tissues of adult C. elegans, building the framework for what’s been dubbed the C. elegans “tissue-ome.”


Creative Minds: Do Celebrity Endorsements Influence Teens’ Health?

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Marie Bragg

Marie Bragg

Marie Bragg is a first-generation American, raised by a mother who immigrated to Florida from Trinidad. She watched her uncle in Florida cope effectively with type 2 diabetes, taking prescription drugs and following doctor-recommended dietary changes. But several of her Trinidadian relatives also had type 2 diabetes, and often sought to manage their diabetes by alternative means—through home remedies and spiritual practices.

This situation prompted Bragg to develop, at an early age, a strong interest in how approaches to health care may differ between cultures. But that wasn’t Bragg’s only interest—her other love was sports, having played on a high school soccer team that earned two state championships in Florida. That made her keenly aware of the sway that celebrity athletes, such as Michael Jordan and Serena Williams, could have on the public, particularly on young people. Today, Bragg combines both of her childhood interests—the influence of celebrities and the power of cultural narratives—in research that she is conducting as an Assistant Professor of Population Health at New York University Langone Medical Center and as a 2015 recipient of an NIH Director’s Early Independence Award.


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