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Under the Microscope: Health Grants Highlight

Welcome to our new health blog series, Under the Microscope: Health Grants Highlight, which will describe the terrific work that our Kenneth Rainin Foundation grantees are doing. This past July, the Foundation awarded 15 new research grants totaling $1.5 million. As the  Health Program Officer and a fellow scientist myself, I am very excited about the innovative and promising research that that the Foundation is supporting.

The impetus for creating this blog series came from questions I frequently get about the type of research the Foundation funds. Our Health program focuses on improving the diagnosis and treatment of Inflammatory Bowel Disease (IBD), with the ultimate goal of finding a cure. We strive to inspire researchers from diverse scientific disciplines to apply their research to the study of IBD. This series will allow us to highlight what our Grantees are doing in their labs and provide an interactive forum for scientific dialogue. We invite you to engage with us and encourage thoughtful comments and questions. The success of this series depends on you and we really want to hear from you.

Our Microscopic Cohabitants

We currently support seven research projects focused on the gut microbiome and our Scientific Advisory Board has chosen Taming the Microbiome as the area of focus for our 2014 Innovations Symposium. In keeping with this theme, the first topic for this series focuses on gut bacteria. People tend to think of disease causing-pathogens when they think about bacteria. However, many researchers have come to appreciate that we are walking communities of microbes and most of them do a lot of good, including helping to digest foods, and making some vitamins and amino acids. The Human Microbiome Project supported by the National Institutes of Health has shown that bacteria live in every nook and cranny of our bodies both inside and out. It is estimated that a healthy human carries about 5 pounds of bacteria in the intestines alone, the equivalent of a two-liter bottle of soda! It has become increasingly clear that these trillions of bacteria that live in our gut have profound effects on our immune system. They play a central role in diseases like IBD and heart disease, and have been recently shown to play a role in obesity.

Although the exact causes of IBD, which includes ulcerative colitis and Crohn’s disease, have not been completely defined, it has become apparent that IBD develops in part as a result of a failure in genetically susceptible individuals to maintain normal host-microbial interactions and mucosal immune homeostasis. Many environmental factors can contribute to the development and pathogenesis of IBD, including nutrition, stress, lifestyle and the composition of intestinal microbiota. Because of this, one can begin to grasp the increasing interest in understanding the fundamental role that intestinal bacterial communities play and how we might manipulate these communities to our benefit.

Genetically Tweaking Probiotics: Designing a More Fit Bug

We are kicking off the topic of the gut microbiome with Dr. Gautam Dantas, Assistant Professor of Pathology and Immunology at Washington University, St. Louis. His research interests lie at the interface of microbial biochemistry, genomics and synthetic biology. His Foundation-funded project is Synthetic Engineering of Enhanced Fitness and Adhesion of Probiotics for the Treatment of Inflammatory Bowel Disease.

Gautam Dantas, Ph.D.

Gautam Dantas, Ph.D.

According to Dantas,  an attractive approach to treating IBD is to modify the gut microbial composition. “Member species of the microbiota within our intestines modulate our immune system and the epithelial barrier function within the intestines, so any perturbation in its composition may result in misregulation and ensuing intestinal disease,” said Dantas.

One way to modify the composition is to deliver live beneficial micro-organisms called probiotics. “Unfortunately, most probiotics are unable to integrate into the host’s established microbiota and persistently colonize the gut. This often leads to relapse of disease symptoms” said Dantas. “Bacterial species introduced to the intestine face significant barriers to survival, including competition from established species, removal from the intestine by peristalsis, innate immune molecules, antimicrobial peptides, and secreted IgA antibodies.”

Dr. Dantas aims to bioprospect the microbiome of healthy individuals for genes that can be used to overcome these barriers and enhance the ability of probiotics to integrate into the host’s microbiota. So far his laboratory has created eight metagenomic libraries from gut microbiota samples, taken at different stages of colonization months after birth, of three human mother-child pairs.

IMG_6496 (2)Dr. Dantas reasons that using samples from multiple families and stages of gut colonization may illuminate redundant adhesion and fitness mechanisms, which should be independent of host genetics, immune function, or baseline microbiota composition. Together these libraries contain the unique metagenomic DNA of roughly >6,000 bacterial genomes. He will utilize the probiotic  Escherichia coli (E. Coli) Nissle 1917 as a functional metagenomic host, which has been previously shown to have potential therapeutic benefit for the prevention of ulcerative colitis relapse during inactive disease. His team will transfer DNA from healthy microbiota and perform a series of metagenomic functional selections to identify genetic modules that improve fitness or adhesion of probiotic strains to gut epithelia, Integration Enhancing Factors (IEFs).

Using a series of in vitro human epithelial cell selection assays to screen for potential IEFs, he will inoculate an established tissue culture system with the probiotic metagenomic library and compare the adhesion or survival to that of the wild-type probiotic. The IEF genes identified from these assays may be directly used, individually or in combination, to engineer a strain of E. Coli Nissle that is more fit in the human intestinal environment. These highly improved probiotics will be then tested in animal models of IBD. According to Dantas, “Introducing fitness-enhancing traits into putative probiotic strains will increase their therapeutic longevity in the gut, improving their ability to regulate intestinal function to treat IBD.”

Dr. Dantas refers to the Foundation’s grant as nothing short of transformative for his research group. “This grant allows us to broaden our primarily basic science expertise into the focused translational area of gastrointestinal disease therapeutics.  It has catalyzed a number of meaningful new collaborations that we would otherwise never even have considered,” said Dantas. “We are excited about exploring this new area and we believe that our work has the potential to meaningfully improve the lives of people suffering from IBD and other inflammatory diseases.”

Dr. Dantas wishes to acknowledge the members of his research team involved with this project, including: Mitchell Pesesky, graduate student in Molecular Microbiology and Microbial Pathogenesis; Molly Gibson, graduate student in Computational and Systems Biology; and Bin Wang, MS, Senior Research Technician.

If you would like to learn more about Dr. Dantas’ work, he will present at the following meetings:

 Selected Publications 

Experimental Approaches for Defining Functional Roles of Microbes in the Human Gut.
Dantas G, Sommer MOA, Degnan PH, Goodman AL. Annu Rev Microbiol. 2013; 67: 459

Novel Resistance Functions Uncovered Using Functional Metagenomic Investigations of Resistance Reservoirs.
Pehrsson EC, Forsberg KJ, Gibson MK, Ahmadi S and Dantas G. Front Microbiol. 2013; 4: 145

The Shared Antibiotic Resistome of Soil Bacteria and Human Pathogens.
Forsberg KJ*, Reyes A*, Wang B, Selleck EM, Sommer MOA, Dantas G. Science. 2012; 337 (6097): 1107

Context Matters – The Complex Interplay Between Resistome Genotypes and Resistance Phenotypes.
Dantas G, Sommer MOA. Curr Op Microbiol. 2012; 15: 577

Functional Characterization of the Antibiotic Resistance Reservoir in the Human Microflora.
Sommer MOA*, Dantas G*, Church GM. Science. 2009; 325 (5944): 1128

Bacteria Subsisting on Antibiotics.
Dantas G*, Sommer MOA*, Oluwasegun RD, Church GM. Science; 2008. 320 (5872): 100

Design of a novel globular protein fold with atomic level accuracy.
Kuhlman B*, Dantas G*, Ireton GC, Varani G, Stoddard BL, Baker D. Science. 2003; 302 (5649): 1364

Kimberly Krivacic, Ph.D.
Program Officer, Health

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