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May 09, 2016
 |  BioCentury  |  Product Development

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How studying bacteria by function is reshaping microbiome therapies

With new papers published by the day and a flurry of big-dollar deals and financings, it's hard to separate the signal from the noise in the microbiome space. The space has become so hot that companies developing products that relate in any way to bacteria, including some OTC probiotics and anti-infectives, have adopted the microbiome label.

Two very interesting approaches driven by new insights into the microbiome as a whole involve mimicking or modifying these microbial communities, either by using bugs themselves as drugs, or by developing traditional therapeutics that reproduce the function of the microbiome.

Over the course of the next year, clinical data from a handful of companies in both categories will begin to separate the wheat from the chaff.

Before about 2010, companies developing bacteria as therapies largely relied on one of two approaches: administration of a single strain of bacteria, or complete transfer of a donor-derived microbiome from a given tissue.

Lower-cost next-generation sequencing allowed the field to move beyond full-scale microbiome transplantation to identify and characterize which bacteria could be harmful or beneficial. This technology enabled creation of a new generation of companies looking to create products around mixtures of bacteria chosen to supplement species or functions lacking in a diseased microbiome.

In addition to blazing a regulatory trial for standardizing and characterizing bacterial mixtures, proof-of-concept (POC) data from these companies may yield insight into how durably microbiome modifications and their subsequent effects on human health can last.

The second group of companies are developing therapies with more traditional modalities based on the identification of the microbiome functions - but not necessarily the species - that play a role in health and disease.

Within the next year, one late-stage readout could confirm early evidence that modulating the microbiome via small molecules can also produce durable and desirable shifts in its composition.

Viewing the microbiome as a collection of functions rather than organisms may make studying it more tractable, because the microbiome includes different bacteria species that play redundant roles.

But there is still a need to better characterize the functional roles the bacteria play. And both sets of companies seeking to modify or replicate the microbiome's functions could benefit from improved animal models and sampling techniques.

Interpreting diversity

The human microbiome is estimated to include more than 10,000 microbial species. An individual's microbiome must perform a specific set of biological tasks to keep its host healthy.

For example, bacteria of the GI tract aid digestion, contribute to development of a mature immune system and protect against overgrowth of harmful organisms by competing for resources.

Disruptions of these microbial communities are associated with disease phenotypes. For example, lower diversity of the gut microbiome has been associated with obesity and inflammatory bowel disease (IBD), and higher diversity in the vagina with bacterial vaginosis.

For some tissues, identifying which bacteria are present and teasing out whether changes in them are the cause or effect of disease processes is relatively straightforward. Osel Inc. Director of Product Development Tom Parks said tissues like the vagina naturally have low microbial diversity, and the same species are often predominant in different people.

The gut is another story. Enterome Bioscience S.A. CEO Pierre Belichard said an individual's gut contains roughly 600 species of bacteria, and the species represented can vary greatly from person to person. This diversity complicates the tasks of identifying which bacteria are present, and determining whether differences in bacterial populations reflect shifts among redundant species, or disease-related changes.

NIH's Human Microbiome Project has so far sequenced over 1,300 strains of bacteria isolated from the human body.

Dirk Gevers, global head of the Janssen Human Microbiome Institute at Johnson & Johnson, noted that microbiome changes associated with disease tend to be more dramatic than normal variability among healthy individuals.

"If you compare what diversity you can capture between a lot of healthy people, and what exists between healthy people and certain diseases, that's at a very different scale. Those signals are much stronger," he said.

However, Bradford McRae, project director of immunology discovery at AbbVie Inc., noted it's not always clear what those dramatic changes mean. "Reduction in diversity in the microbiome and overgrowth of bacteria are known to be associated with pro-inflammatory responses, but it's not known if those changes precede the signs of clinical disease and are causative of that, or if they occur as a result of the disease secondary to disease processes," he said.

Further complicating that understanding is the challenge of differentiating microbiome components from host cells and tissues. Yet early data sets have started to provide POC that manipulating the microbiome is a viable way to treat disease.

For example, 2013 saw studies showing that transplanting human fecal microbiota into mice could induce obesity and its associated metabolic phenotypes, and human data from a controlled study suggesting the procedure could treat recurrent C. difficileinfection.

Early data linking the microbiome to...

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