Mike's Blog

One advantage of a long career in medicine is the opportunity to witness the emergence and development of new concepts that advance from curious observations to routine clinical practice. One area of growing interest is the microbiome and its potential for manipulation. Its reach now appears far broader than we once imagined. As research has progressed, the range of diseases potentially impacted by the microbiome has expanded to encompass nearly all of Harrison’s Principles of Internal Medicine, including, but not limited to, neurodegenerative disorders, inflammatory diseases, psychiatric disorders, metabolic disorders, cancer, periodontal disease, and even glaucoma. The implication is hard to ignore: the microbiome is not just a bunch of hard to pronounce microorganisms—it is foundational to human physiology and health.

Microbiome manipulation can take many forms. And we have already manipulated it, often unintentionally. Antibiotics have an obvious negative impact on the microbiome with recovery from a single treatment course requiring months to return to baseline. Early efforts at microbiome manipulations have tended to involve transferring a ‘healthy’ microbiome into someone with a medical condition, typically chronic Clostridioides difficile (C. diff) infection, colloquially termed ‘repoopulation.’ A recent Stat article describes the origins and early days of fecal microbiota transplant (FMT): “had a whiff of the DIY: doctors and their blenders, making one bespoke slurry at a time.” The progression from bespoke home brew ‘milkshakes’ to the non-profit OpenBiome to FDA products (at a cost of ~$10K) is detailed. Left out of the currently available options are children under 12 as a result of the FDA approvals; the Stat article details that struggle and ongoing challenges making this therapy available to everyone.

In terms of developing potential microbiome manipulations, the issues and challenges are readily apparent. Defining a ‘normal’ or ‘healthy’ microbiome is not trivial, as well as how we even analyze microbiomes. The National Institute of Standards and Technology (NIST) has been addressing this issue over the past ten years. Methodologies for generating ‘repoopulation’ cocktails (since they can’t be manufactured) and ensuring some measure of consistency, as well as testing for all the potential pathogens lurking in the human gut must also be validated, not to mention defining specific, measurable clinical outcomes (we can assess for lack of specific signs and symptoms, but defining someone as having a ‘healthy’ gut is unclear). As such, it’s easy to see why the FDA has concerns. One limitation is that the FDA only reviews data submitted to it; they do not simply read the existing literature (I’m aware of one instance when this happened). So even with a cohort study involving more than 5000 patients, the best the FDA can do is to ‘practice enforcement discretion’ until an entity elects to pursue a specific clinical indication.

Microbiome manipulation is likely to evolve towards more complex protocols that could include combinations of prebiotics, probiotics, and even bacteriophage cocktails. There is even the possibility of developing drugs (which may be of interest to pharma, particularly since bioavailability won’t be an issue) to specifically target the microbiome, not in an antimicrobial fashion, but rather selectively inhibiting normal microbial physiology as has already been observed with berberine and statins. Unfortunately, the for-profit pharma sector will struggle to monetize most types of approaches, and thus, development will lag.

Microbiome manipulation is but one example of evolving 21^st century science that offers tremendous potential for human health rather than simply a stellar bottom line but will require considerable translational science effort to reduce to routine clinical practice. The interdisciplinary nature of the work aligns perfectly with the CTSA, especially given the likely lack of interest on the part of traditional for-profit players. In addition, there has already been some effort by the CTSA community in this area. Rather than merely removing a ‘bottleneck,’ let’s consider forging a whole new mode of delivering preventive and interventional health care?

What I’m reading: Raising Steam by Terry Pratchett, a volume in his hugely successful Discworld franchise. The steam engine is developed and introduced into this world. The varied spinoffs that develop as a result of this technology, as well as pushbacks toward this technology are fascinating to observe along with the geopolitical implications that must be addressed. Nothing happens in isolation. Everything unfolds in Pratchett’s incomparable comedic style along with his masterful wordplay. 

Everything is magic when you don’t know what it is. Your sliding rule is a magic wand to most people.

Terry Pratchett, Raising Steam