Human Microbiome, Part II - Microbial Product Characterization (see “Microbiome: Part 2” in Innovation Brainstorm ideas)

Title of proposed idea: Human Microbiome, Part II - Microbial Product Characterization (see “Microbiome: Part 2” in Innovation Brainstorm ideas)

Nominator: NIH Institutes/Centers

 Major obstacle/challenge to overcome: The Human Microbiome Project has dramatically increased our understanding of the diversity and genetics of the microbial constituents of the human body.  The next and even bigger step is to move beyond sequencing and organism identification to functional understanding of the microbiome and  its relationship to a broad spectrum of autoimmune, infectious, metabolic, and other diseases.  At a big-picture level, the challenge is to understand how commensal bacteria, probiotics, and their products may act and interact at mucosal surfaces and throughout the body to alter physiology and pathogenesis. For instance, it is known that intestinal microbes produce vitamins and minerals and provide them to the host, and that carbohydrate fermentation produces short-chain fatty acids that can alter host absorption of calcium, magnesium, and phosphorus.  Intriguingly, microbial products from one organism also can alter the gene expression and the functional metabolome of other resident microbes.  As an example, in a model gut system the exogenously administered probiotic Bifidobacterium longum was shown to expand the variety of polysaccharides targeted for degradation by Bacteroides thetaiotaomicron, which is a prominent member of the adult human gut microbiota.¹ These and other examples speak to the importance of identifying and understanding the protein, small molecule, and metabolite products of those microbes, and the relationship of these to beneficial or adverse functions of the microbiome and probiotics administered with an intention of altering it.

Emerging scientific opportunity ripe for Common Fund investment:  The Human Microbiome Project has provided the capacity to determine the composition of the microbiome and observe associations between the microbiome and a spectrum of disorders ranging from intestinal disease to obesity and from cystic fibrosis to cancer.  This has set the stage for movement toward a more functional understanding of the microbiome-human relationship.  A detailed characterization, including both identification and determination of function, of the small molecule, protein, and metabolic products of human microflora has become necessary to advance the field.   Characterization of microbial products would focus initially those produced by the most common oral and gut commensals.  Additionally, early on it is vital to study the organisms used as probiotics with the intent of altering the oral and gut flora because altered microflora may concurrently alter gut micro-ecology, intestinal barrier function, metabolic activity of the host, and modulate mucosal and systemic immune function.  A comprehensive analysis of microbial products, beginning now with organisms identified in the first stage of the HMP as being associated with health or disease and then expanded over time, is required in order to appreciate and predict the effects of changes in the microbiome resulting from such causes as antibiotic use, disease, or probiotic administration. 

Common Fund investment that could accelerate scientific progress in this field:  The Common Fund could accelerate the potential transformative impact of the microbiome sequencing data by establishing projects that would focus on the microbial products of both common human flora and potential probiotic organisms.  This initiative would encompass the following undertakings:

• Establish repository capacity and production facilities for strains of organisms that would be made available to investigators upon request.
• Determine sequences at the strain level since different strains of the same bacterial species have been shown to exhibit differential metabolic and immunoregulatory activity.
• Determine and catalog microbial small molecule and protein products.
• Assess strain-specific metabolomics.
• Undertake functional analysis including toxicity of microbial products and metabolites.  This would involve assembly and conduct of a panel of screening assays for effects on other microbes such as changes in their metabolome or the total gut metabolome or effects on the host such as changes in gut barrier function or immune activity.
• Provide information for regulatory agencies thus facilitating work in humans.

Potential impact of Common Fund investment: Understanding of the organisms and their products and metabolites, and providing characterized and standardized resources to investigators, would be invaluable.  There would be clarity as to genotype, phenotype, and function of microbes under study.  Such comprehensive analyses of commensal organism and probiotic products are a prerequisite for elucidating how the oral and intestinal mucosa respond to their resident and transient flora.  Detailed assessment of a repertoire of products of common microbes also provides a method for rational study of the resultant mucosal and systemic effects (both beneficial and adverse) of conditions such as antibiotic use, weight loss/gain, and disease.  Further, it is crucial for the eventual understanding of the potential impact of probiotics on health since one might match the correct probiotic strain with the desired clinical outcome, be it immune function, barrier function or metabolism.   Finally, these analyses may yield new therapeutic targets or insights into dietary interventions; and understanding variation in microbial products will shed light on how an imbalance in our microbiota may contribute to disease.

¹Sonnenburg JL, Chen CT, Gordon JI Genomic and metabolic studies of the impact of probiotics on a model gut symbiont and host. PLoS Biol. 4(12):e413, 2006.