Discoveries regarding the role of the microbiome in human health and disease have been emerging with stunning frequency. While each new discovery builds upon the last, occasionally a point is reached at which, in the aggregate, researchers can begin to refocus their efforts, identifying distinct approaches to modulating and/or protecting our internal flora in order to preserve and enhance our own well-being. For example, it has been suggested recently that the gut microbiome may facilitate weight loss in response to polyphenols found in tea, that specific elements of the gut microbiota can modulate the response to treatments for metastatic melanoma, that the composition of the gut microbiome alters the toxicity of chemotherapeutics in colon cancer, and that proton pump inhibitors (PPIs) may promote alcoholic liver disease by a mechanism mediated through the gut microbiome. These discoveries, taken together, suggest that the ways in which drugs are administered to a functioning microbiome may merit at least as much consideration as the ways in which we might alter such a microbiome.

It is relatively easy to think about tackling the role of the microbiome in human health in terms of interventions calculated to enhance the growth of beneficial bacteria, such as by administration of probiotic bacteria themselves, or by the administration of prebiotics. It is perhaps less intuitive to think about the ways in which the microbiome, and especially the gut microbiome, can affect the metabolism and efficacy of drugs or dietary small molecule compounds that are intended to be administered to our somatic tissues. However, as the recent discoveries indicate, the microbiome may be involved in determining drug efficacy (as with certain metastatic melanoma treatments), or may be a source of side effects or toxicities (as in the case of PPIs occasionally promoting alcoholic liver disease or microbially-mediated irinotecan toxicity in colon cancer). As well, the microbiome may be the site of action of a small molecule compound, as in the case of tea polyphenols that facilitate weight loss.

One consequence of these insights is that it is possible to consider the microbiome to be a distinct “druggable target” in the development of small molecule therapeutics or conventional biologics. Rather than attempting to directly influence the composition of the microbiome, it appears to be possible in some cases to use small molecules to alter the behavior of the microbiome, much in the way conventional drug development seeks to manipulate the behavior of somatic tissues. This, by extension, moves a subset of microbiome-facing treatments into the realm of more conventional drug discovery processes--and familiar treatment modalities.

The impact of such a shift could potentially be enormous. While there is considerable uncertainty regarding the regulatory status of live-cell biotherapeutics for the modulation of the microbiome in specific conditions, evaluation of the safety and efficacy of small molecules and conventional biologics follows a well-worn path. Likewise, IP protection for small molecules can employ well established strategies. For example, patent protection for live organisms, as well as bacterial extracts, media, and prebiotics, requires patent practitioners and inventors to wrestle with some unique issues that can be less pressing in the small molecule realm. Questions surrounding the patent eligibility of natural products, for example, are almost certain to affect the availability of patent protection for live bacteria, lysates, prebiotics, and bacterially-derived compounds. Small molecules, peptides, and novel biologics, on the other hand, will often have an easier time meeting patent eligibility hurdles, progressing through much more traditional composition-of-matter and method-of-use patents.

The microbiome clearly should be considered alongside somatic targets in evaluating drug efficacy and side effects, as well as in developing drug targets in the first place. Treating the microbiome as an organ that can be approached using conventional drug design principles offers a powerful additional avenue for treating disease within existing treatment paradigms. It is likely that innovators seeking to target the microbiome in this way will find the availability of established regulatory and IP strategies smooths the way to the clinic as well.