An ambitious, recently funded 5-year project seeks to shed light on the effects of gut bacteria on host biology, with the ultimate goal of constructing transplant-ready synthetic communities of gut microbes to prevent and treat various diseases.
In the healthy human body, microbial cells outnumber human cells by about 10 to 1. Accumulating evidence suggests that gut microbes play an important role in human health and disease. Yet research on the role of bacterial symbionts in human biology is largely correlative, and relatively little is known about interactions between the host and microbiota at the molecular level. Most efforts to address this question focus on identifying individual molecules responsible for particular phenotypes of interest.
“Small-molecule metabolites are one of the major ways in which our resident microbial cells are communicating with our human cells and influencing numerous aspects of human biology,” said Justin Sonnenburg from Stanford University, who studies the basic principles that govern interactions within the intestinal microbiota and between the microbiota and the host. “There are thousands of these chemical messengers absorbed into the human bloodstream, yet only a handful have been studied in detail due to the exceptional difficulty in unraveling the complex biology.”
A project recently funded by the National Institutes of Health (NIH) may soon change this paradigm. With the help of a 2016 NIH Director’s Pioneer Award, a team led by Michael Fischbach from the University of California, San Francisco, will generate a complete map of the top 100 molecules from the gut microbiome. The most abundant molecules produced by gut microbes vary widely in concentration among individuals, can accumulate in host circulation, and are present at levels that match or exceed the concentration of a typical small-molecule drug. This ensemble of high-concentration molecules, to which we are exposed daily, is likely to be a major driver of human biology and disease.
“Advances in understanding the universe of small molecules produced by our gut microbes will result in new therapeutic opportunities,” Sonnenburg said. “Our resident microbes have, over the course of our co-evolutionary history, developed sophisticated means of modulating human biology, and Michael’s project promises to bring these interactions to light. The result will undoubtedly be intriguing and likely propel the field toward harnessing the power of gut microbes to treat and prevent diseases.”
Gardening our Microbiomes
The 5-year project—awarded more than 1 million dollars for the 2016 fiscal year—offers a solution that runs counter to the trend of genomics-driven approaches, which dominate the fields of natural product discovery and microbiome research. Fischbach’s team will analyze stool samples collected from male and female volunteers representing a broad cross-section of ages, races, and ethnicities. By combining old-fashioned microbiology with state-of-the-art analytical chemistry, Fischbach and his team will systematically determine the bacterial species that produce each of the top 100 molecules.
Using the rich information derived from metabolic profiling, the researchers will apply genetic and biochemical techniques to identify the genes responsible for synthesizing the top 100 molecules. They will then devise a computational algorithm to predict metabolic output directly from metagenomic sequence data and test their predictions using simple synthetic communities. In the end, this research could enable the construction of transplant-ready synthetic communities of gut microbes that produce custom cocktails of desired molecules optimized to prevent and treat particular disorders, such as gastrointestinal diseases, obesity, and heart disease.
“Knowing what the most abundant molecules are in the gut and who makes them is a fundamental insight into our biology that we’re simply missing at present,” said Rob Knight from the University of California, San Diego, who uses and develops advanced computational and experimental techniques to study microbial ecosystems of the human body. “As we discover more about how these molecules change in health and disease, this study will provide the baseline knowledge of how to optimize them by gardening our microbiomes, as well as targets for drugs that might act on microbial enzymes rather than human ones.”
Decoding the Molecular Language
This work will enable Fischbach’s team to knock out the function of each gene, transplant the genetically engineered bacteria into the guts of laboratory mice, and then study how the lack of each particular bacterial gene affects the health of the mice. One specific goal is to understand how polysaccharides produced by Bacteroides affect the host immune system. In a few years, the researchers hope to construct their first synthetic community of gut bacteria and gear up for clinical trials to test its safety and ability to improve human health.
“I expect the study to greatly contribute to the field, as it will take us one step closer to achieving a mechanistic, molecular-level understanding of host-microbiome interactions,” said Eran Elinav from the Weizmann Institute of Science, who examines interactions between the innate immune system, the intestinal microbiota, and their effects on health and disease. “It is exactly work like this that will enable the field to characterize how disturbances in the molecular language dictating host–microbiome crosstalk may contribute to the risk of developing common human diseases, such as obesity and its complications, inflammatory bowel disease, and even cancer and neuro-degenerative disease.”
According to Elinav, Fischbach’s approach is highly innovative because it combines metagenomics and metabolomics to identify and characterize the function of abundant microbiome-associated molecules. “These molecules are promising in not only bearing a potential to be used as biomarkers for a variety of common microbiome-associated diseases, but may be bioactive, that is, have biological effects in the human body. Thus, identifying these molecules, their biosynthetic pathways, and modes of activity may yield a plethora of new therapeutics and diagnostics,” he said.
Such an ambitious project may not have been attempted previously because the necessary tools and knowledge for addressing these complex questions are rare, and perhaps unique to the Fischbach lab, Sonnenburg said. “Michael’s project will greatly accelerate the pace of discovery through a powerful approach of combining chemical analytical approaches, with molecular biology and genomics/metagenomics,” Sonnenburg said. “The innovation is in the wide range of biological and chemical tools and insight that Michael and his lab have amassed, which are required to make headway on these challenging questions.”
Moving forward, the project will provide a template that other researchers can follow, as well as a strong foundation of knowledge that can be mobilized to support numerous aspects of microbiome science, Sonnenburg said. “In addition, Michael’s lab develops computational software so other researchers with less expertise in this area can rely on algorithms to identify important and unexplored features of the microbiome.”