Clinical and Public Health Microbiology

NIH Workshop:
The Human Microbiome – Conference Round-Up for August 17, 2017

CONFERENCE ROUND-UP  August 17, 2017

The Human Microbiome: Emerging Themes at the Horizon of the 21st Century

Microbes inhabit just about every part of the human body, outnumbering human cells by ten to one. The ten-year, National Institutes of Health (NIH) Common Fund Human Microbiome Project was established to understand how microbial communities impact human development, physiology, immunity, brain development, and behavior, and to create research resources for this emerging field.

This 2017 NIH-wide microbiome workshop was organized by a planning committee of the trans-NIH Microbiome Working Group (TMWG)1, which includes program staff from the 19 NIH Institutes, Centers and Offices that support human microbiome research through their extramural portfolios. The TMWG is interested in taking stock of where the microbiome field stands after NIH’s ten-year investment in the Human Microbiome Project and evaluating what is needed for this field to advance over the next decade. This meeting will cover advances that reveal specific ways that microbiota influence the physiology of the host, in both health and disease, and how the microbiota may be manipulated at the community, population, organismal, or molecular level to maintain and/or improve host health.

Below are summaries of only a few of the sessions that occurred today.  To hear all the sessions, go to the NHGRI web site (https://www.genome.gov/) and access the livestream on demand recordings for each day of the conference.  Each session lasted 15 minutes to give more speakers a chance to contribute and to give attendees as large an overview of the field as possible.

Keynote II:  The Gut Microbiota and Childhood Undernutrition: Looking at Human Development from a Microbial Perspective

(Jeffrey I. Gordon, presenter – Washington University, St. Louis)

Dr. Gordon is fond of the African proverb “If you want to go fast, go alone, if you want to go far, go together.”  Much of his research funding comes from the Bill and Melinda Gates Foundation, which forces scientists to look at the conditions in which human beings live and encourages people to respect and care for one another.  He thinks that microbiome research is an inherently interdisciplinary field that looks at very challenging and vexing problems and creates opportunities to evolve how we do science.  Higher knowledge is democratized and available for everyone on the bench and we have to figure out how to evolve the algorithms and create collaborations between labs.  He wants everyone to encourage our institutions to invest in these scientific ecosystems where we can tinker and think like they did in the Edison lab.

Dr. Gordon’s lab is focused on the healthy growth of children and childhood undernutrition, which is the leading cause of death in people under age 5.  Therapeutic food cannot solve all the problems that undernutrition produces, and can’t prevent stunting, developmental abnormalities, and immune dysfunction in later life.

Healthy development of the gut microbiota is linked to healthy children.  If the gut microbiome is disrupted, enteropathogens find niches and create an enteropathogen burden, the gut mucosal immune system doesn’t develop properly, and host cell lineages that affect organs outside the gut are impaired.  Gordon would like to see the scientific community become good microbial farmers and be able to 1) influence the trajectory of gut microbiota to ensure healthy development, and 2) be able to repair dysfunctions caused by undernutrition.

Gordon and his colleagues conducted studies in Dhaka in Bangladesh and Mirapor in India.  Weight for age scores were often two to three standard deviations below normal and as many as 50,000 people were existing in a five square-mile area.  Monthly fecal samples were collected and the researchers found 24 taxa with age discriminatory strains.  Some were country-specific and site-specific.

They saw 18-month old children with 8 month microbiome ages, and realized that current therapeutic foods were not designed to repair these underdeveloped microbiomes, which produced persistent stunting and bone abnormalities.  Most of the time there were slight improvements followed by regression.

The team performed a study where undernourished children were randomized to three types of therapeutic foods and followed for 12 months (every month for six and then bimonthly).  Blood samples were taken at admission, discharge, and at six months.  The diet had no effect on stunting and there was persistent microbial immaturity.  When serum proteins were examined, they found that therapeutic food reduced the high levels of osteoclastic activity found at admission, but procollagen peptide type 1 was not improved and leptins were not improved.  The rampant glycolysis and fatty acid oxidation found at admission were reduced by the new diet, but six months after discharge the children started losing ground again, although glycolysis levels were lower because insulin and IgF levels stayed up.

The team wants to explore whether gut microbiota immaturity is related to pathogens or undernutrition.  They also wanted to develop metrics for assessing growth, ways of separating IgA plus and negative fractions to isolate anaerobic microbes, and explore the organisms they found that could oppose the severe acute malnutrition (SAM) phenotype.

Another problem they want to solve is how to examine microbiota along the length of the gut.  They think that capsules can sample and monitor the life of the gut and want to encourage bioengineers to develop them so they can determine the biogeography and spatial co-occurrence of microbes through the intestines.

SAM produces environmental enteric dysfunction (EED), which includes loss of villi height and other intestinal damage.  The team is conducting research on SAM children that involves performing endoscopies on their upper GI tract to determine whether there are EED discriminatory microbes and where they colonize the gut.  They also want to explore the relationship between breast milk, polysaccharides and the gut microbiota, and sialic acid levels and the gut microbiota.  Children cannot make sialic acid on their own but must get it from another source.  It is essential for bone formation and growth and a variety of other metabolic activities.

The team also wanted to encourage the use of traditional complementary foods because they are the product of years of maternal observation about what helps children grow.  Microbially enriched complementary foods could be developed using age and growth discriminatory strains of helpful bacteria.  The effect of processing on these bacteria must be explored.  Gordon suggested that, if problems arise, alternatives be tested in human beings, not animal.  He also thought the order of nutrient presentation was important.

The following are questions Gordon and his team want to answer.  Can we repair microbiota immaturity and how long will it last?  What are the underpinnings of microbial succession?  Can we moderate or mitigate enteropathogen invasion?  Can we repair the gut microbiome after perturbations such as antibiotics?

Gordon thinks we are on the threshold of a revolution about the molecular components of food that will determine the essential nutrients foods possess, how processing destroys those nutrients, the role of chewing in nutrient release, and the roles of social and cultural issues in nutrition and health.  He wants to evaluate the differences diet and weaning age make on the health of developing children, and use the lens of anthropology to determine how differences in lifestyle affect child health and development.

Gut Microbiota, Diet, Chronic Inflammation, and Metabolic Syndrome

(Andrew Gewirtz, presenter – Georgia State University)

Dr. Gewirtz and his team wanted to share four messages.

  1. 1) Failure to keep gut microbiota in check results in multiple flavors of gut inflammation, including colitis and metabolic syndrome.  In germ-free conditions, the symptoms go away.  Altered microbes are more aggressive and can encroach on the host.  Dysglycemia and higher A1c scores were correlated with higher levels of bacteria.
  2. 2) A healthy gut requires proper nourishment of the microbiota.  Diversity = health.  The addition of immulin, which is digestible, to the diet of laboratory mice is therapeutic, while the addition of cellulose, which is indigestible, is not.
  3. 3) Be really careful about telling people what to eat.  When immulin supplements were maintained for six months, the mice developed liver cancer.
  4. 4) Some common food additives can alter the gut microbiome    Polysorbate 80 and carboxymethylcellulose – emulsifiers used since the 1960s – promote gut dysfunction.  They increase the fat in the diet and that results in increased body weight.  In germ-free conditions, there was no effect.  The two additives promote bacterial encroachment and misbehavior.

The team thought that we need to understand how major and minor food components affect the microbiota and gene expression, and wanted to find an open-source diet that can maintain healthy gut microbiota.  As far as lab studies are concerned, the very clean lab conditions make results less relevant than a more microbially diverse environment.

Understanding and Predicting the Impact of Antibiotic Therapy on the Developing Pediatric Microbiota and Resistome

(Gautam Dantas, presenter – Washington University in St. Louis)

The Gaps = How do we accurately define the omic studies needed to define a problem?  What do you call particular molecular entities and is naming them important?  How do post-hoc analyses impact data?  There should be more pattern recognition leading to predictions in future studies.

Dantas and his colleagues are interested in how microbial communities respond to perturbation.   Antibiotics are the greatest perturbation for microbial life because they are designed to kill microbes.  What collateral damage have these perturbations produced?

Antibiotic resistance in pathogens is our greatest infectious disease challenge.  It produces 700,000 deaths per year now and will produce several million by 2050.  In 2050, there will be 86,000 antibiotic resistance deaths during the three-day course of a scientific meeting such as this conference.  The cost will run into several hundred trillion dollars.

Dantas’ lab uses functional metagenomics rather than shotgun sequencing because it produces a catalogue of resistance genes that can be transferred into model communities.  He and his colleagues take an ecological view of antibiotic resistance and the effects of antibiotics on the gut microbiome.  They want to understand the translational dynamics of these phenomena and how they produce new pathogens.

Antibiotic resistomes in soil are extensive but not set up to horizontally transfer genes.  Some microbes are facile at crossing resistance barriers.  Studies in slums in El Salvador and Lima, Peru, which duplicate the environment of 2/3 of the world’s population, showed that human microbiota are structured through lifestyle and habitat with little transfer between humans and other species.  The exceptions were chicken coops in El Salvador and wastewater treatment plants in Lima that revealed active horizontal gene transfer.

The first three years of life are when the body’s ecosystem is established.  Premature babies are most at risk for never developing competent gut microbiomes.  They are so subject to infection that they receive huge amounts of antibiotics in the ICU that wreck their developing ecosystems.  Dantas’s lab studied 84 preterm infants for the first 2.5 months they were in the ICU and there were huge differences between the gut microbiota of babies who only received antibiotics during the first few days of life and those who received antibiotics for at least a month.  The latter had greatly reduced microbial diversity and many of the bacteria that were present were pathogenic.  Specific antibiotics affected specific taxa and specific antibiotic resistance genes were increased.

Dantas’s team wants to explore what happens later in life when pediatric patients, especially preterm infants, who received antibiotics are past their acute illness or vulnerability.  They would like to conduct a study where they can take samples through at least the first two years of life from both infants who received antibiotics in the ICU and healthy, matched controls.

Leaving Limbo: Stepping Back to Build a Strong Foundation of Mechanism and Stepping Forward to Dietary Interventions in Humans

(Justin Sonnenburg, presenter – Stanford University)

Dr. Sonnenburg feels that the rush towards microbiome interventions has left basic science behind.  He would like to see more funding for studies of non-pathogenic interactions in the gut and would like scientists to use healthy humans as a model system for studying the microbiome.

If our diet is deficient in good nutrients, our microbes attack the mucin layer of the intestine and start eating us to get them.  Spatial organization of microbes in the gut is important.

There is incompatibility between our genomes and our gut microbiomes, probably because there has been a very quick transition in industrialized countries from a high-fiber to a low-fiber diet.  It was not possible to get funding to study microbiomes in people in different cultures around the world, so Sonnenburg’s team has concentrated on working with the Hadza tribe in Tanzania, who are one of the last fulltime hunter-gatherer cultures in the world and can show us what our gut microbiome looked like for all but the last hundred or so years of our existence.  The researchers found seasonal variations (dry-wet-dry), great microbial diversity, and new taxa not seen in the industrial world.

To test some of their hypotheses, the researchers gave mice human microbiota and randomized them to high-fat and high-fiber diets for four generations.  The mice on the high-fiber diets quickly lost a lot of bacteria.  When fiber was put back into their diet, the bacteria came back, but not all of them and it was harder to pass them on to the next generation.

Sonnenburg’s team has a number of questions they want to answer.  What would happen if the Hadza ate nothing but a wet-season diet for a number of generations?  Can we put lost bacteria back into the gut?  Should we do so?  If we do it, should we do it naturally by adding the right food or purposefully by adding the bacteria directly?

The researchers work at the Center for Human Microbiome Studies at Stanford that explores the role of diet in the microbiome.  Machines ID the predictive elements, and the predictive elements show them what mechanisms they should be studying.  The Center uses immune profiling, omics data, and clinical/cognitive/behavioral tests in addition to standard measures to evaluate results.

The team hopes to be able to tell people what to eat to prevent disease and would like to see other researchers explore this and not look only for drug cures.  They think changing dietary habits is doable but difficult.  By preference, the Hadza would eat only meat and honey, not the high fiber diet they eat by necessity.  Put into a supermarket, they would make the same bad choices we do.

Testing Diet – Gut Microbiome Interactions: Use of Controlled Feeding Studies in Humans

(Johanna W. Lampe, presenter – Fred Hutchinson Cancer Research Center)

The issues in controlled feeding studies include the fact that they involve complex exposures to many different elements, instead of controlled laboratory experiments with fixed parameters and genetically similar subjects.  Although we give the food to the participants, what they consume has many variables that we don’t think about with our casual attitude towards diet.  If the studies are done on a metabolic ward they are certainly elegant, but they are also complex and expensive.  Often the participants are students writing theses so it limits the generalizability of the data.  People have called them rat studies done in humans and they don’t represent real-world conditions.  You can control the intervention, the background diet, and the dosing; but the studies end up being useful but limited.  You are focusing on biomarkers of effect, but you can also develop biomarkers of exposure and bacterial activity.  Your subjects will probably mutiny after 6-8 weeks so you must depend on intermediary biomarkers because you can’t carry out the diet until it produces disease.

Why bother with dietary studies?  Proposing food choices is clinically important and dietary studies offset single nutrient lab approaches because nutrients are interconnected.

One study put African Americans on a native South African diet and native South Africans on an African American diet.  Although this was a short-term study, biopsies at the end showed increases in inflammatory markers and pre-cancerous markers in the people fed an African American diet.  When the data was analyzed multinomically, even bigger differences were found, including variations in taxa.

Dr. Lampe encouraged her colleagues to engage with researchers who do feeding studies because they store lots of samples so they can continue to explore their results from many different angles.

In spite of the common reactions to changes in diet, Lampe said that natural heterogeneity and individual metabolism affected the results of feeding studies more than any other single factor.

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