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Posted on by Dr. Francis Collins
While sitting in microbiology class as a college sophomore, Elaine Hsiao was stunned to learn that the human gut held between as much as 6 pounds of bacteria—twice the weight of an adult human brain. She went on to learn during her graduate studies in neurobiology that these microbes had co-evolved with humans and played important roles in our bodies, aiding digestion and immune function, for example. But more intriguing to her, by far, was new research that suggested that gut bacteria might even be influencing our thoughts, moods, and behavior.
Now a senior research fellow at the California Institute of Technology, Hsiao is launching her own effort to explore how these microbes can affect brain function—a very creative endeavor made possible through NIH’s Early Independence Award program—also known as the “skip the postdoc” award.
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
At NIH, we have a front row seat to remarkable advances in science and technology that help Americans live longer, healthier lives. By studying the role that the mouth and saliva can play in the transmission and prevention of disease, the National Institute of Dental and Craniofacial Research (NIDCR) contributed to our understanding of infectious agents like the coronavirus SARS-CoV-2, the cause of COVID-19. While these and other NIH-supported advances undoubtedly can improve our nation’s health as a whole, not everyone enjoys the benefits equally—or at all. As a result, people’s health, including their oral health, suffers.
That’s a major takeaway from Oral Health in America: Advances and Challenges, a report that NIDCR recently released on the status of the nation’s oral health over the last 20 years. The report shows that oral health has improved in some ways, but people from marginalized groups —such as those experiencing poverty, people from racial and ethnic minority groups, the frail elderly, and immigrants—shoulder an unequal burden of oral disease.
At NIDCR, we are taking the lessons learned from the Oral Health in America report and using them to inform our research. It will help us to discover ways to eliminate these oral health differences, or disparities, so that everyone can enjoy the benefits of good oral health.
Why does oral health matter? It is essential for our overall health, well-being, and productivity. Untreated oral diseases, such as tooth decay and gum disease, can cause infections, pain, and tooth loss, which affect the ability to chew, swallow, eat a balanced diet, speak, smile, and go to school and work.
Treatments to fix these problems are expensive, so people of low socioeconomic means are less likely to receive quality care in a timely manner. Importantly, untreated gum disease is associated with serous systemic conditions such as diabetes, heart disease, and Alzheimer’s disease.
A person experiencing poverty also may be at increased risk for mental illness. That, in turn, can make it hard to practice oral hygiene, such as toothbrushing and flossing, or to maintain a relationship with a dental provider. Mental illnesses and substance use disorders often go hand-in-hand, and overuse of opioids, alcohol, and tobacco products also can raise the risk for tooth decay, gum disease, and oral cancers. Untreated dental diseases in this setting can cause pain, sometimes leading to increased substance use as a means of self-medication.
Research to understand better the connections between mental health, addiction, and oral health, particularly as they relate to health disparities, can help us develop more effective ways to treat patients. It also will help us prepare health providers, including dentists, to deliver the right kind of care to patients.
Another area that is ripe for investigation is to find ways to make it easier for people to get dental care, especially those from marginalized or rural communities. For example, the COVID-19 pandemic spurred more dentists to use teledentistry, where practitioners meet with patients remotely as a way to provide certain aspects of care, such as consultations, oral health screenings, treatment planning, and education.
Teledentistry holds promise as a cost-saving approach to connect dentists to people living in regions that may have a shortage of dentists. Some evidence suggests that providing access to oral health care outside of dental clinics—such as in schools, primary care offices, and community centers—has helped reduce oral health disparities in children. We need additional research to find out if this type of approach also might reduce disparities in adults.
These are just some of the opportunities highlighted in the Oral Health in America report that will inform NIDCR’s research in the coming years. Just as science, innovation, and new technologies have helped solve some of the most challenging health problems of our time, so too can they lead us to solutions for tackling oral health disparities. Our job will not be done until we can improve oral and overall health for everyone across America.
Oral Health in America: Advances and Challenges (National Institute of Dental and Craniofacial Research/NIH)
Note: Acting NIH Director Lawrence Tabak has asked the heads of NIH’s Institutes and Centers (ICs) to contribute occasional guest posts to the blog to highlight some of the interesting science that they support and conduct. This is the 11th in the series of NIH IC guest posts that will run until a new permanent NIH director is in place.
Human skin is home to diverse ecosystems including bacteria, viruses, and fungi. These microbial communities comprise hundreds of species and are collectively known as the skin microbiome. The skin microbiome is thought to play a vital role in fending off disease-causing microorganisms (pathogens), boosting barrier protection, and aiding immune defenses.
Maintaining a balanced skin microbiome involves a complex and dynamic interplay among microorganisms, immune cells, skin cells, and other factors. In general, bacteria far outnumber viral, fungal, or other microbial species on the skin. Bacterial communities, which are strongly influenced by conditions such as skin moisture, temperature, and pH, vary widely across the body. For example, facial cheek skin hosts mostly Cutibacterium along with a bit of the skin fungus Malassezia. The heel is colonized by different types of bacteria including Staphylococcus and Corynebacteria.
In some diseases, such as acne and eczema, the skin microbiome is altered. Typically, this means an increase in pathogenic microorganisms and a decrease in beneficial ones. An altered skin microbiome can also be associated with inflammation, severe disease symptoms, and changes in the human immune system.
Heidi H. Kong is working to understand the role of the skin microbiome in health and disease. She is a senior investigator in the Intramural Research Program at NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and an adjunct investigator at NIH’s National Cancer Institute (NCI).
More than a decade ago, Kong and Julie A. Segre, an intramural researcher at NIH’s National Human Genome Research Institute, analyzed the microbial makeup of healthy individuals. Kong swabbed the skin of these healthy volunteers in 20 different sites, from the forehead to the toenail. The study revealed that the surface of the human body provides various environmental niches, depending on whether the skin is moist, dry, or sebaceous (oily). Different bacterial species predominate in each niche. Kong and Segre were particularly interested in body areas that have predilections for disease. For example, psoriasis is often found on the outside of elbows and knees, and the back of the scalp.
Earlier this year, Kong and Segre published another broad analysis of the human skin microbiome  in collaboration with scientists at the European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), United Kingdom. This new catalog, called the Skin Microbial Genome Collection, is thought to identify about 85 percent of the microorganisms present on healthy skin from 19 body sites. It documents more than 600 bacterial species—including 174 that were discovered during the study—as well as more than 6,900 viruses and some fungi, including three newly discovered species.
Kong’s work has provided compelling evidence that the human immune system plays a role in shaping the skin microbiome. In 2018, she, Segre, and colleagues from the intramural programs of NCI and NIH’s National Institute of Allergy and Infectious Diseases analyzed skin from eight different sites on 27 people with a rare primary immunodeficiency disease known as DOCK8 deficiency .
People with the condition have recurrent infections in the skin, sinuses, and airways, and are susceptible to different cancers. Kong and colleagues found that the skin of people with DOCK8 deficiency contains significantly more DNA viruses (90 percent of the skin microbiome on average) than people without the condition (6 or 7 percent of the skin microbiome).
Other researchers are hoping to leverage features of the microbiome to develop targeted therapies for skin diseases. Richard L. Gallo, a NIAMS grantee at the University of California, San Diego, is currently focused on acne and eczema (also called atopic dermatitis). Acne is associated with certain strains of Cutibacterium acnes (C. acnes, formerly called Propionibacterium acnes or P. acnes). Eczema is often associated with Staphylococcus aureus (S. aureus).
Severe cases of acne and eczema are commonly treated with broad-spectrum antibiotics, which wipe out most of the bacteria, including beneficial species. The goal of microbiome-targeted therapy is to kill only the disease-associated bacteria and avoid increasing the risk that some strains will develop antibiotic resistance.
In 2020, Gallo and colleagues identified a strain of Staphylococcus capitis from healthy human skin (S. capitis E12) that selectively inhibits the growth of C. acnes without negatively impacting other bacteria or human skin cells . S. capitis E12 produces four different toxins that act together to target C. acnes. The research team created an extract of the four toxins and tested it using animal models. In most cases, the extract was more potent at killing C. acnes—including acne-associated strains—than several commonly prescribed antibiotics (erythromycin, tetracycline, and clindamycin). And, unlike antibiotics, the extract does not appear to promote drug-resistance, at least for the 20 generations observed by the researchers.
Eczema is a chronic, relapsing disease characterized by skin that is dry, itchy, inflamed, and prone to infection, including by pathogens such as S. aureus and herpes virus. Although the cause of eczema is unknown, the condition is associated with human genetic mutations, disruption of the skin’s barrier, inflammation-triggering allergens, and imbalances in the skin microbiome.
In 2017, Gallo’s research team discovered that, in healthy human skin, certain strains of Staphylococcus hominis and Staphylococcus epidermis produce potent antimicrobial molecules known as lantibiotics . These beneficial strains are far less common on the skin of people with eczema. The lantibiotics work synergistically with LL-37, an antimicrobial molecule produced by the human immune system, to selectively kill S. aureus, including methicillin-resistant strains (MRSA).
Gallo and his colleagues then examined the safety and therapeutic potential of these beneficial strains isolated from the human skin microbiome. In animal tests, strains of S. hominis and S. epidermis that produce lantibiotics killed S. aureus and blocked production of its toxin.
Gallo’s group has now expanded their work to early studies in humans. In 2021, two independent phase 1 clinical trials [5,6] conducted by Gallo and his colleagues investigated the effects of these strains on people with eczema. These double-blind, placebo-controlled trials involved one-week of topical application of beneficial bacteria to the forearm of adults with S. aureus-positive eczema. The results demonstrated that the treatment was safe, showed a significant decrease in S. aureus, and improved eczema symptoms in most patients. This is encouraging news for those hoping to develop microbiome-targeted therapy for inflammatory skin diseases.
As research on the skin microbiome advances on different fronts, it will provide deeper insight into the multi-faceted microbial communities that are so critical to health and disease. One day, we may even be able to harness the microbiome as a source of therapeutics to alleviate inflammation, promote wound healing, or suppress certain skin cancers.
 Integrating cultivation and metagenomics for a multi-kingdom view of skin microbiome diversity and functions. Saheb Kashaf S, Proctor DM, Deming C, Saary P, Hölzer M; NISC Comparative Sequencing Program, Taylor ME, Kong HH, Segre JA, Almeida A, Finn RD. Nat Microbiol. 2022 Jan;7(1):169-179.
 Expanded skin virome in DOCK8-deficient patients. Tirosh O, Conlan S, Deming C, Lee-Lin SQ, Huang X; NISC Comparative Sequencing Program, Su HC, Freeman AF, Segre JA, Kong HH. Nat Med. 2018 Dec;24(12):1815-1821.
 Identification of a human skin commensal bacterium that selectively kills Cutibacterium acnes. O’Neill AM, Nakatsuji T, Hayachi A, Williams MR, Mills RH, Gonzalez DJ, Gallo RL. J Invest Dermatol. 2020 Aug;140(8):1619-1628.e2.
 Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis. Nakatsuji T, Chen TH, Narala S, Chun KA, Two AM, Yun T, Shafiq F, Kotol PF, Bouslimani A, Melnik AV, Latif H, Kim JN, Lockhart A, Artis K, David G, Taylor P, Streib J, Dorrestein PC, Grier A, Gill SR, Zengler K, Hata TR, Leung DY, Gallo RL. Sci Transl Med. 2017 Feb 22;9(378):eaah4680.
 Development of a human skin commensal microbe for bacteriotherapy of atopic dermatitis and use in a phase 1 randomized clinical trial. Nakatsuji T, Hata TR, Tong Y, Cheng JY, Shafiq F, Butcher AM, Salem SS, Brinton SL, Rudman Spergel AK, Johnson K, Jepson B, Calatroni A, David G, Ramirez-Gama M, Taylor P, Leung DYM, Gallo RL. Nat Med. 2021 Apr;27(4):700-709.
 Use of autologous bacteriotherapy to treat Staphylococcus aureus in patients with atopic dermatitis: A randomized double-blind clinical trial. Nakatsuji T, Gallo RL, Shafiq F, Tong Y, Chun K, Butcher AM, Cheng JY, Hata TR. JAMA Dermatol. 2021 Jun 16;157(8):978-82.
Acne (National Institute of Arthritis and Musculoskeletal and Skin Diseases/NIH)
Atopic Dermatitis (NIAMS)
Julie Segre (National Human Genome Research Institute/NIH)
Gallo Lab (University of California, San Diego)
[Note: Acting NIH Director Lawrence Tabak has asked the heads of NIH’s Institutes and Centers (ICs) to contribute occasional guest posts to the blog to highlight some of the cool science that they support and conduct. This is the fifth in the series of NIH IC guest posts that will run until a new permanent NIH director is in place.]