Reprocessing Of Phase 1 Hmp Sequence Data
A significant portion of HMP analysis data was generated with older tools that are no longer considered current state-of-the-art. Therefore, as part of our work under the CFDE, we will be re-processing all 16S and whole metagenome sequencing data from the first phase of the HMP using new pipelines incorporating state-of-the-art tools, including those described above in the Tools and Protocols Section. New analysis results will be made available through our HMPDACC resource and eventually the CFDE.
Future Areas Of Research
The microbiome is a living dynamic environment where the relative abundance of species may fluctuate daily, weekly, and monthly depending on diet, medication, exercise, and a host of other environmental exposures. However, scientists are still in the early stages of understanding the microbiomes broad role in health and the extent of problems that can occur from an interruption in the normal interactions between the microbiome and its host.
Some current research topics:
- How the microbiome and their metabolites influence human health and disease.
- What factors influence the framework and balance of ones microbiome.
- The development of probiotics as a functional food and addressing regulatory issues.
Specific areas of interest:
- Factors that affect the microbiome of pregnant women, infants, and the pediatric population.
- Manipulating microbes to resist disease and respond better to treatments.
- Differences in the microbiome between healthy individuals and those with chronic disease such as diabetes, gastrointestinal diseases, obesity, cancers, and cardiovascular disease.
- Developing diagnostic biomarkers from the microbiome to identify diseases before they develop.
- Alteration of the microbiome through transplantation of microbes between individuals .
Common Fund Data Ecosystem
In addition to the HMP, the NIH Common Fund has supported numerous other programs that also generate large quantities of data and have associated Data Coordination Centers , LINCS ). A new Common Fund project, the Common Fund Data Ecosystem , has been developed to provide an overarching cloud-based data infrastructure and framework that will support past, present and future Common Fund project DCCs. The CFDE, in association with the NIH STRIDES program , is developing a cloud-based platform where DCCs can store, and users can access and compute on, Common Fund DCC metadata. Part of this effort is the development of a cross-cutting metadata model that will store metadata associated with all DCC assets. For DCCs that have reached the end of their funded time, not only metadata, but also primary and derived data, will be housed by the CFDE. Some of these data may be controlled-access. A CFDE data portal is under development that will provide controlled access, via portal query and API, to both public and protected data. This will be managed through a system that authenticates users based on whether they have been granted access permissions by the relevant NIH Data Access Committees.
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Global Diversity Of The Human Microbiome
Although the 6.5 meter human digestive tract consists of three organsthe stomach, small intestine, and large intestinemost human microbiome research focuses on the microbial community of the large intestine as read out through the stool. This community harbors by far the greatest microbial biomass of any organ or surface of the human body. Each milliliter of the large intestine holds approximately 1011 microbial cells compared to 108 cells in the small intestine . Typically, researchers turn to non-invasive fecal samples as proxies for the distal colon microbiome. These samples contain a mixture of microbes and human colonocytes from along the length of the digestive tract and have a similar, albeit distinct, composition to intestinal biopsies .
First, Western microbiomes consist of 15 to 30% fewer species than non-Western microbiomes . One proposal, the disappearing microbiome hypothesis, puts forth that technological and cultural changes accompanying industrialization lead to a disappearing microbiome . In lieu of building a time machine, the one way to evaluate this hypothesis is to turn to ancient DNA .
Second, Western microbiomes lack certain species that consistently occur in non-Western microbiomes. The most striking example is the spiral bacteria in the genus Treponema, which appears in the stool of numerous non-Western populations who utilize different subsistence strategies, including hunting and gathering and agriculture .
Development Of New Approaches For Cultivation Of The Previously Uncultivable
Though cultures of human commensal microorganisms are needed for studies of microbial physiology and metabolism, many of these microorganisms were not previously available because most earlier culture work was focused on pathogens and because traditional culture methods were used. Several research groups, particularly those that study the oral microbiome, have developed new approaches to the cultivation of the previously uncultivable members of the microbiome. For example, one group has recently succeeded in the cultivation of a human oral TM7 phylotype , an important member of the oral microbiome with a highly reduced genome . In this particular case, TM7x can only be cultivated in the direct presence of a cultivation partner . A similar situation exists with Desulfobulbus oralis, a microorganism associated with periodontitis . This microorganism was first isolated via co-culture with another microorganism, Fusobacterium nucleatum. Unlike TM7x, which seems to require direct cell-cell contact with its cultivation partner, D. oralis was cultivated using F. nucleatum cell-free spent medium as a media supplement. These and other kinds of novel approaches to cultivation which recognize that microbes do not live in isolation in nature but share substrates and cofactors for growth, have contributed new cultured isolates and strains to the global reference database of human-associated commensal microorganisms.
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Timing Of Sample Storage
It often is impractical to immediately analyze fresh samples in microbiome research. As a result, many samples are preserved through storage at 80°C. It remains unclear whether freezing samples significantly affects the resulting community profiles. Work by Bahl et al. compared frozen and fresh human stool samples from the same donors using quantitative PCR and found significant differences in the Firmicutes to Bacteroidetes ratio. However, subsequent work by Fouhy et al. comparing frozen and fresh stool samples using both culture and DNA sequence-based approaches showed no significant differences in the relative abundances of bacteria at the phylum or family level. At the genus level, there was only minor evidence suggesting that the relative abundances of Faecalibacterium and Leuconostoc may be biased due to sample freezing. Taken together, these results have helped reinforce the current standard of immediately freezing samples at 80°C upon collection .
The Role Of The Human Microbiota
Most members of the human microbiota benefit humans by providing them with traits that they would not otherwise possess. Some microorganisms found in the human gut, for instance, obtain nutrients from ingested food in return for assisting with the breakdown of food or preventing the colonization of the gut by harmful bacteria. There are, however, many microorganisms in the human microbiota that are closely related to pathogenic organisms or are themselves capable of becoming pathogenic. Examples include bacterial species of the genera Staphylococcus, Streptococcus, Enterococcus, Klebsiella, Enterobacter, and Neisseria.
Scientists studying obesity have detected an increased abundance of Prevotella and Firmicutes bacteria and of methanogenic archaea in obese individuals relative to normal-weight persons and persons who have undergone gastric bypass surgery. Scientists suspect that these microorganisms are more efficient at harvesting carbohydrates from food than are the types of microorganisms that dominate the gut flora of normal-weight individuals. The extra nutrients are then stored in the body as fat.
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Gaps And Opportunities Which Emerged From This Portfolio Analysis
This section completes the portfolio analysis by highlighting some of the technical needs and knowledge gaps which remain for this field to be able to advance over the next decade and so that the outcomes from human microbiome research can ultimately be incorporated into efforts to support health and treat disease.
Different Treatments For Crohns Disease In Pediatric Patients Have Distinct Effects On The Gut Microbiome
Changes in diet and application of antibiotics and/or anti-inflammatories are the typical interventions used as the standards of care for the treatment of Crohns disease , a subtype of inflammatory bowel disease. One major characteristic of CD is an imbalance in the normal composition of the microbiota in comparison to healthy controls.; A recent study from Human Microbiome Project awardee Dr. Frederic Bushman and colleagues at the University of Pennsylvania sought to systematically separate the effects of these interventions on the gut microbiomes of a cohort of pediatric CD patients.
Each intervention independently affected the microbiome in CD patients. In particular, antibiotic use seemed to worsen dysbiosis by reducing the abundances of some microbes, increasing the abundances of fungi or both, thus aggravating the condition. Anti-inflammatories, on the other hand, reduced gut microbiota dysbiosis, thereby potentially supporting recovery from CD. Certain defined diets resulted in rapid changes in the gut microbiome suggesting diet may also be an effective treatment for CD.
Inflammation, Antibiotics, and Diet as Environmental Stressors of the Gut Microbiome in Pediatric Crohn’s Disease. Lewis JD, Chen EZ, Baldassano RN, Otley AR, Griffiths AM, Lee D, Bittinger K, Bailey A, Friedman ES, Hoffmann C, Albenberg L, Sinha R, Compher C, Gilroy E, Nessel L, Grant A, Chehoud C, Li H, Wu GD, Bushman FD. Nature. 14;October;2015. 18: 489-500.
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New Approaches To Study Microbe
There is still much to understand about how microbe-microbe, inter-kingdom microbial interactions, and microbial community level interactions occur, and how these interactions may play a role in human health and disease. Some of these knowledge gaps would benefit from studies of cultured microorganisms of human-associated microbes but these are still not broadly available. For example, many microbial members identified in the HMP healthy cohort metagenomic reference database do not yet have known cultured representative strains or isolates , and this presents a significant technological gap for microbial physiology studies. This issue is being addressed to some degree in the oral microbiome field through new methods for laboratory cultivation of oral taxa. However, a broader range of microbiological and engineering approaches are needed to isolate and cultivate representative members of the human microbiome.
Direct Observation Of The Human Microbiome
Most microbiome analyses have focused on DNA or RNA sequencing or metabolomic analyses, but useful insights into microbiome composition, function, and spatial organization can be gained by using a variety of imaging technologies. Transmission and scanning electron microscopy can be used to visualize microbial community organization in fixed samples but is not well suited to resolving individual taxa or traits in a complex community. Fluorescence in situ hybridization can be used to evaluate the taxonomy, location, and organization of microbial community members in fixed microbiome samples. In the FISH method, fluorescently labeled DNA probes that recognize a gene sequence within targeted microbial taxa are hybridized to a fixed intact microbiome sample and imaged to visualize the location of the microbial cells that contain the corresponding DNA sequence with micrometer resolution. It can be performed with probes that recognize single taxa or multiplexed to target diverse taxa in a single sample . Fluorescence-activated cell sorting can be used similarly to quantify and sort microbial cells that are dissociated from a microbiome sample and that display a phenotype that is detectable with a fluorescent marker, such as an exogenous fluorescent probe or genetically encoded fluorescent protein .
Suggested Citation:Environmental Chemicals, the Human Microbiome, and Health Risk: A Research Strategy
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Normal Microbiota As Host Defense
The human microbiome is now recognized as a major host defense against bacterial pathogens by providing colonization resistance, maintaining a balance of commensals to pathogens, and by priming the immune system .5 Altering or disrupting the normal microbiota by antibiotics facilitates the expansion of enteric pathogens as Clostridium difficile and Salmonella typhimurium or selection of antibiotic-resistant members of the microbiome. Similarly, changes in human physiology, for example, exposure of skin to elevated temperatures and humidity, chronic stress, host immune suppression, or active behavioral changes, such as smoking, can cause a commensal-to-pathogen switch. Recent studies have demonstrated that certain resident microbiota can resist pathogen colonization and infection. For example, matched volunteers were inoculated with Haemophilus ducreyi into the arms, and the subsequent infection either resolved or resulted in formation of abscesses; characterization of the skin microbiome before, during, and after the experimental inoculation showed that the microbiomes of those with pustule formation and of those with resolved infection were distinct and influenced the course of the H. ducreyi infection.6
Michael J. Orlich, … Sarah Jung, in, 2017
Considerations In Sampling The Human Microbiome
The first step in a microbiome study typically involves the collection of stabilized microbial biomass specimens that will be used and analyzed in various assays. Each sampling method for human-associated microbial community types has strengths and weaknesses that are driven by the dramatically different microbial ecologies in or on the body. The methods that have been established for gathering a sample of sufficient biomass for each major body site are described here, and limitations of each approach are noted.
Suggested Citation:Environmental Chemicals, the Human Microbiome, and Health Risk: A Research Strategy
the presence of human cells in the sample. Other sample types, such as mucosal brushing or rectal swabs, are also possible but are less well studied with respect to protocol consistency and community representation .
All human microbiome sampling protocols are sensitive to batch effectstechnical, not biologic, differences that arise from many stages of the sampling and data-generation process . Such effects can make data from multiple studies difficult to compare and, in the worst case, can introduce subtle differences that result in misleading conclusions. Gross differences in population structure, geography, or environmental conditions can change measured microbial communities. Differences in how samples are collected and processed can strongly influence microbiome
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Can Diet Affect Ones Microbiota
In addition to family genes, environment, and medication use, diet plays a large role in determining what kinds of microbiota live in the colon. All of these factors create a unique microbiome from person to person. A high-fiber diet in particular affects the type and amount of microbiota in the intestines. Dietary fiber can only be broken down and fermented by enzymes from microbiota living in the colon. Short chain fatty acids are released as a result of fermentation. This lowers the pH of the colon, which in turn determines the type of microbiota present that would survive in this acidic environment. The lower pH limits the growth of some harmful bacteria like Clostridium difficile. Growing research on SCFA explores their wide-ranging effects on health, including stimulating immune cell activity and maintaining normal blood levels of glucose and cholesterol.
Be aware that a high intake of prebiotic foods, especially if introduced suddenly, can increase gas production and bloating. Individuals with gastrointestinal sensitivities such as irritable bowel syndrome should introduce these foods in small amounts to first assess tolerance. With continued use, tolerance may improve with fewer side effects.
If one does not have food sensitivities, it is important to gradually implement a high-fiber diet because a low-fiber diet may not only reduce the amount of beneficial microbiota, but increase the growth of pathogenic bacteria that thrive in a lower acidic environment.
An Interview With Jeff Leach Founder Of The Human Food Project
His opinions on health and nutrition have appeared in the;New York Times,;San Francisco Chronicle,;Sydney Morning Herald;and his peer-reviewed research has been published in the;British Journal of Nutrition,;European Journal of Clinical Nutrition,;BioScience and Microflora,;Journal of Archaeological Science, Public Health Nutrition;and many others.
As part of his efforts at the Human Food Project, Jeff has spent a great deal of time doing research with rural pastoralists and hunter-gatherer groups in East and Southern Africa.
We are pleased to have Jeff join us to share some of his insights on the microbiome.
How did you get interested in studying the microbiome, and how has your background prepared you for this type of research?I;got interested in the human microbiome about 12-15 years ago after my infant daughter was diagnosed as a type I diabetic. At the time, very few peopleoutside of researcherswere talking about the role of microbes in human health. Following a little research, I quickly found that microbes ‘might’ have played a role in her journey.
Since the Hadza live outside 24/7and are exposed to an extraordinary diversity of microbes from soil, water, butchered animals and plants we have found that they harbor nearly twice the gut microbes as the average Westerner.
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What Is A Healthy Microbiome New Analysis Suggests That One Size Does Not Fit All
The typical healthy person is inhabited with trillions of microbes. To better understand the role of these organisms across our body sites, we must to catalog and analyze what organisms are there and how they interact with our own cells. A new analysis of healthy microbiomes has found that each persons microbiome is unique. Therefore, two healthy people may have very different microbial communities but still be healthy. Strikingly, the researchers found that although unique, certain communities could be used to predict characteristics. For example, whether you were breastfed as an infant and even your level of education could be predicted based on microbial communities across varying body sites. The analysis also showed that microbial communities from varying body sites on the same individual were predictive for others. For example, gut communities could be predicted by examining the oral community, even though these communities are vastly different from each other. Taken together, this new analysis will help pave the way for future studies that can begin to use microbial communities as a basis for personalizing therapies and possibly to assess the risk for certain diseases.
Read the University of Michigan press release; here
Watch Dr. Schloss explain his research;;here;
Ding T, Schloss PD. Dynamics and associations of microbial community types across the human body. Nature. 2014 Apr 16. PMID 24739969