Posted on by Dr. Francis Collins
Basic research in biology generates fundamental knowledge about the nature and behavior of living systems. It is generally impossible to predict exactly where this line of scientific inquiry might lead, but history shows that basic science almost always serves as the foundation for dramatic breakthroughs that advance human health. Indeed, many important medical advances can be traced back to basic research that, at least at the outset, had no clear link at all to human health.
One exciting example of NIH-supported basic research is the Human Microbiome Project (HMP), which began 12 years ago as a quest to use DNA sequencing to identify and characterize the diverse collection of microbes—including trillions of bacteria, fungi, and viruses—that live on and in the healthy human body.
The HMP researchers have subsequently been using those vast troves of fundamental data as a tool to explore how microbial communities interact with human cells to influence health and disease. Today, these explorers are reporting their latest findings in a landmark set of papers in the Nature family of journals. Among other things, these findings shed new light on the microbiome’s role in prediabetes, inflammatory bowel disease, and preterm birth. The studies are part of the Integrative Human Microbiome Project.
If you’d like to keep up on the microbiome and other basic research journeys, here’s a good way to do so. Consider signing up for basic research updates from the NIH Director’s Blog and NIH Research Matters. Here’s how to do it: Go to Email Updates, type in your email address, and enter. That’s it. If you’d like to see other update possibilities, including clinical and translational research, hit the “Finish” button to access Subscriber Preferences.
As for the recent microbiome findings, let’s start with the prediabetes study . An estimated 1 in 3 American adults has prediabetes, detected by the presence of higher than normal fasting blood glucose levels. If uncontrolled and untreated, prediabetes can lead to the more-severe type 2 diabetes (T2D) and its many potentially serious side effects .
George Weinstock, The Jackson Laboratory for Genomic Medicine, Farmington, CT, Michael Snyder, Stanford University, Palo Alto, CA, and colleagues report that they have assembled a rich new data set covering the complex biology of prediabetes. That includes a comprehensive analysis of the human microbiome in prediabetes.
The data come from monitoring the health of 106 people with and without prediabetes for nearly four years. The researchers met with participants every three months, drawing blood, assessing the gut microbiome, and performing 51 laboratory tests. All this work generated millions of molecular and microbial measurements that provided a unique biological picture of prediabetes.
The picture showed specific interactions between cells and microbes that were different for people who are sensitive to insulin and those whose cells are resistant to it (as is true of many of those with prediabetes). The data also pointed to extensive changes in the microbiome during respiratory viral infections. Those changes showed clear differences in people with and without prediabetes. Some aspects of the immune response also appeared abnormal in people who were prediabetic.
As demonstrated in a landmark NIH study several years ago , people with prediabetes can do a lot to reduce their chances of developing T2D, such as exercising, eating healthy, and losing a modest amount of body weight. But this study offers some new leads to define the biological underpinnings of T2D in its earliest stages. These insights potentially point to high value targets for slowing or perhaps stopping the systemic changes that drive the transition from prediabetes to T2D.
The second study features the work of the Inflammatory Bowel Disease Multi’omics Data team. It’s led by Ramnik Xavier and Curtis Huttenhower, Broad Institute of MIT and Harvard, Cambridge, MA. 
Inflammatory bowel disease (IBD) is an umbrella term for chronic inflammations of the body’s digestive tract, such as Crohn’s disease and ulcerative colitis. These disorders are characterized by remissions and relapses, and the most severe flares can be life-threatening. Xavier, Huttenhower, and team followed 132 people with and without IBD for a year, collecting samples of their gut microbiomes every other week along with biopsies and blood samples for a total of nearly 3,000 samples.
By integrating DNA, RNA, protein, and metabolic analyses, they followed precisely which microbial species were present. They could also track which biochemical functions those microbes were capable of performing, and which functions they actually were performing over the course of the study.
These data now offer the most comprehensive view yet of functional imbalances associated with changes in the microbiome during IBD flares. These data also show how those imbalances may be altered when a person with IBD goes into remission. It’s also noteworthy that participants completed questionnaires on their diet. This dataset is the first to capture associations between diet and the gut microbiome in a relatively large group of people over time.
The evidence showed that the gut microbiomes of people with IBD were significantly less stable than the microbiomes of those without IBD. During IBD activity, the researchers observed increases in certain groups of microbes at the expense of others. Those changes in the microbiome also came with other telltale metabolic and biochemical disruptions along with shifts in the functioning of an individual’s immune system. The shifts, however, were not significantly associated with people taking medications or their social status.
By presenting this comprehensive, “multi-omic” view on the microbiome in IBD, the researchers were able to single out a variety of new host and microbial features that now warrant further study. For example, people with IBD had dramatically lower levels of an unclassified Subdoligranulum species of bacteria compared to people without the condition.
The third study features the work of The Vaginal Microbiome Consortium (VMC). The study represents a collaboration between Virginia Commonwealth University, Richmond, and Global Alliance to Prevent Prematurity and Stillbirth (GAPPS). The VMC study is led by Gregory Buck, Jennifer Fettweis, Jerome Strauss,and Kimberly Jefferson of Virginia Commonwealth and colleagues.
In this study, part of the Multi-Omic Microbiome Study: Pregnancy Initiative, the team followed up on previous research that suggested a potential link between the composition of the vaginal microbiome and the risk of preterm birth . The team collected various samples from more than 1,500 pregnant women at multiple time points in their pregnancies. The researchers sequenced the complete microbiomes from the vaginal samples of 45 study participants, who gave birth prematurely and 90 case-matched controls who gave birth to full-term babies. Both cases and controls were primarily of African ancestry.
Those data reveal unique microbial signatures early in pregnancy in women who went on to experience a preterm birth. Specifically, women who delivered their babies earlier showed lower levels of Lactobacillus crispatus, a bacterium long associated with health in the female reproductive tract. Those women also had higher levels of several other microbes. The preterm birth-associated signatures also were associated with other inflammatory molecules.
The findings suggest a link between the vaginal microbiome and preterm birth, and raise the possibility that a microbiome test, conducted early in pregnancy, might help to predict a woman’s risk for preterm birth. Even more exciting, this might suggest a possible way to modify the vaginal microbiome to reduce the risk of prematurity in susceptible individuals.
Overall, these landmark HMP studies add to evidence that our microbial inhabitants have important implications for many aspects of our health. We are truly a “superorganism.” In terms of the implications for biomedicine, this is still just the beginning of what is sure to be a very exciting journey.
 Longitudinal multi-omics of host-microbe dynamics in prediabetes. Zhou W, Sailani MR, Contrepois K, Sodergren E, Weinstock GM, Snyder M, et. al. Nature. 2019 May 29.
 National Diabetes Statistics Report, 2017, Center for Disease Control and Prevention (Atlanta, GA)
 Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study. Diabetes Prevention Program Research Group.Lancet Diabetes Endocrinol.2015 Nov;3(11):866-875.
 Multi-omics of the gut microbial ecosystem in inflammatory bowel disease. Lloyd-Price J, Arze C. Ananthakrishnan AN, Vlamakis H, Xavier RJ, Huttenhower C, et. al. Nature. 2019 May 29.
 The vaginal microbiome and preterm birth. Fettweis JM, Serrano MG, Brooks, JP, Jefferson KK, Strauss JF, Buck GA, et al. Nature Med. 2019 May 29.
Insulin Resistance & Prediabetes (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)
Crohn’s Disease (NIDDK/NIH)
Ulcerative colitis (NIDDK/NIH)
Preterm Labor and Birth: Condition Information (Eunice Kennedy Shriver National Institute of Child Health and Human Development/NIH)
Global Alliance to Prevent Prematurity and Stillbirth (Seattle, WA)
Prediabetes Study: Common Fund; National Institute of Dental and Craniofacial Research; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Human Genome Research; National Center for Advancing Translational Sciences
Inflammatory Bowel Disease Study: Common Fund; National Institute of Diabetes and Digestive and Kidney Diseases; National Center for Advancing Translational Sciences; National Institute of Human Genome Research; National Institute of Dental and Craniofacial Research
Preterm Birth Study: Common Fund; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development
Posted on by Dr. Francis Collins
More than half of U.S. adults take dietary supplements . 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 . 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 . 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.
 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.
 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].
 Vitamin Supplementation to Prevent Cancer and CVD: Preventive Medication. U.S. Preventive Services Task Force, February 2014.
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
Posted on by Dr. Francis Collins
Obesity—which affects about 4 in 10 U.S. adults—increases the risk for lots of human health problems: diabetes, heart disease, certain cancers, and even anxiety and depression . It’s also been associated with increased accumulation of senescent cells, which are older cells that resist death even as they lose the ability to grow and divide.
Now, NIH-funded researchers have found that when lean mice are fed a high-fat diet that makes them obese, they also have more senescent cells in their brain and show more anxious behaviors . The researchers could reduce this obesity-driven anxiety using so-called senolytic drugs that cleared away the senescent cells. These findings are among the first to provide proof-of-concept that senolytics may offer a new avenue for treating an array of neuropsychiatric disorders, in addition to many other chronic conditions.
As we age, senescent cells accumulate in many parts of the body . But cells can also enter a senescent state at any point in life in response to major stresses, such as DNA damage or chronic infection. Studies suggest that having lots of senescent cells around, especially later in life, is associated with a wide variety of chronic conditions, including osteoporosis, osteoarthritis, vascular disease, and general frailty.
Senescent cells display a “zombie”-like behavior known as a senescence-associated secretory phenotype (SASP). In this death-defying, zombie-like state, the cells ramp up their release of proteins, bioactive lipids, DNA, and other factors that, like a zombie virus, induce nearby healthy cells to join in the dysfunction.
In fact, the team behind this latest study, led by James Kirkland, Mayo Clinic, Rochester, MN, recently showed that transplanting small numbers of senescent cells into young mice is enough to cause them weakness, frailty, and persistent health problems. Those ill effects were alleviated with a senolytic cocktail, including dasatinib (a leukemia drug) and quercetin (a plant compound). This drug cocktail overrode the zombie-like SASP phenotype and forced the senescent cells to undergo programmed cell death and finally die.
Previous research indicates that senescent cells also accumulate in obesity, and not just in adipose tissues. Moreover, recent studies have linked senescent cells in the brain to neurodegenerative conditions, including Alzheimer’s disease, and showed in mice that dasatinib and quercetin helps to alleviate neurodegenerative disease [4,5]. In the latest paper, published in the journal Cell Metabolism, Kirkland and colleagues asked whether senescent cells in the brain also could explain anxiety-like behavior in obesity.
The answer appears to be “yes.” The researchers showed that lean mice, if allowed to feast on a high-fat diet, grew obese and became more anxious about exploring open spaces and elevated mazes.
The researchers also found that the obese mice had an increase in senescent cells in the white matter near the lateral ventricle, a part of the brain that offers a pathway for cerebrospinal fluid. Those senescent cells also contained an excessive amount of fat. Could senolytic drugs clear those cells and make the obesity-related anxiety go away?
To find out, the researchers treated lean and obese mice with a senolytic drug for 10 weeks. The treatment didn’t lead to any changes in body weight. But, as senescent cells were cleared from their brains, the obese mice showed a significant reduction in their anxiety-related behavior. They lost their anxiety without losing the weight!
More preclinical study is needed to understand more precisely how the treatment works. But, it’s worth noting that clinical trials testing a variety of senolytic drugs are already underway for many conditions associated with senescent cells, including chronic kidney disease [6,7], frailty , and premature aging associated with bone marrow transplant .
As a matter of fact, just after the Cell Metabolism paper came out, Kirkland’s team published encouraging though preliminary, first-in-human results of the previously mentioned senolytic drug dasatinib in 14 people with age-related idiopathic pulmonary fibrosis, a condition in which lung tissue becomes damaged and scarred . Caution is warranted as we learn more about the associated risks and benefits, but it’s safe to say we’ll be hearing a lot more about senolytics in the years ahead.
 Adult obesity facts (Centers for Disease Control and Prevention)
 Obesity-induced cellular senescence drives anxiety and impairs neurogenesis. Ogrodnik M et al. Cell Metabolism. 2019 Jan 3.
 Aging, Cell Senescence, and Chronic Disease: Emerging Therapeutic Strategies. Tchkonia T, Kirkland JL. JAMA. 2018 Oct 2;320(13):1319-1320.
 Tau protein aggregation is associated with cellular senescence in the brain. Musi N, Valentine JM, Sickora KR, Baeuerle E, Thompson CS, Shen Q, Orr ME. Aging Cell. 2018 Dec;17(6):e12840.
 Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Bussian TJ, Aziz A, Meyer CF, Swenson BL, van Deursen JM, Baker DJ. Nature. 2018 Oct;562(7728):578-582.
 Inflammation and Stem Cells in Diabetic and Chronic Kidney Disease. ClinicalTrials.gov, Sep 2018.
 Senescence in Chronic Kidney Disease. Clinicaltrials.gov, Sep 2018.
 Alleviation by Fisetin of Frailty, Inflammation, and Related Measures in Older Adults (AFFIRM-LITE). Clinicaltrials.gov, Dec 2018.
 Hematopoietic Stem Cell Transplant Survivors Study (HTSS Study). Clinicaltrials.gov, Sep 2018.
 Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. Justice JN, Nambiar AN, Tchkonia T, LeBrasseur K, Pascual R, Hashmi SK, Prata L, Masternak MM, Kritchevsky SB, Musi N, Kirkland JL. EBioMed. 5 Jan. 2019. [Epub ahead of print]
Healthy Aging (National Institute on Aging/NIH)
Video: Vail Scientific Summit James Kirkland Interview (Youtube)
James Kirkland (Mayo Clinic, Rochester, MN)
NIH Support: National Institute on Aging; National Institute of Neurological Disorders and Stroke
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