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Out of order: Inverted focus?
July 2019
by Randall C Willis  |  Email the author
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When I was a kid, coming home for lunch was a harrowing experience. Not because I lived in a bad neighborhood or because I was mistreated, but rather because I never knew what to expect when I walked through the door.
 
My mother, you see, simply could not leave the living room furniture alone.
 
No sooner would I throw my jacket onto the chair than I would have to pick my jacket off the floor, the chair having found its way to the other side of the room or even into another room altogether.
 
Although my brothers and I were quite willing to watch television from any and all angles, my mother seemed incapable of relaxing in her environment and spent much of her day trying to make her environment fit her ever-shifting needs.
 
This memory was brought to the fore recently as I read a recent issue of New Scientist (June 8-14), as it seems biomedical research and healthcare increasingly take on my mother’s traits.
 
The magazine highlighted research undertaken by Yale’s Michael Zimmerman and colleagues to understand the potential influence of gut microbiota on a range of drugs, seeing if microbial metabolism might help to at least partly explain the heterogeneity seen in patient responses.
 
Combining high-throughput genetic analysis and mass spectrometry, the researchers found that almost two-thirds of the 271 drugs tested were metabolized by at least one of the 76 bacterial strains examined. And every strain examined metabolized anywhere from 11 to 95 drugs.
 
“Given that the authors tested a broadly representative panel of drugs, the scale of these results is remarkable because it raises the possibility that most drugs are modified by the microbiota,” commented Northeastern University’s Kim Lewis and Holobiome’s Philip Strandwitz in an accompanying “News & Views” article. “This type of testing could also be a useful way of singling out drugs that would probably be deactivated by the microbiota.”
 
Within a fortnight of those Nature publications, Harvard’s Vayu Maini Rekdal and colleagues published just such an effort in Science, where they screened gut microbiomes to identify two bacteria—Enterococcus faecalis and Eggerthella lenta—involved in the metabolism of the Parkinson’s drug L-dopa to an inactive form. They then screened a series of tyrosine mimics and found one that could inhibit L-dopa metabolism in vitro. The compound also increased peak serum concentrations of L-dopa in mice colonized with E. faecalis.
 
Brilliant. Further evidence from well-designed experiments that gut microbes can metabolize the compounds we ingest, in some cases influencing therapeutic efforts.
 
Not to minimize the science in any way, but we have just described a living room of furniture and the functions of many individual pieces.
 
It is what comes later in the discussion, however, that reminds me of my mother’s domestic restlessness.
 
“The finding that our gut bacteria may affect so many drugs hints at the possibility of changing our microbiomes to increase a drug’s efficacy or reduce side effects,” wrote New Scientist’s Adam Vaughn. “The goal would be to change patients to suit their drugs, rather than the other way round.”
 
“Such issues highlight the complexity of considering a person’s microbiota when trying to take a personalized medicine approach,” wrote Lewis and Strandwitz. “Adjusting the microbiota to suit our needs, including achieving individually tailored approaches to tackling drug metabolism, is probably where this field is heading.”
 
“We have used chemical knowledge and interdisciplinary tools to decipher the molecular mechanisms by which gut bacteria interfere with the treatment of Parkinson’s disease,” Rekdal and colleagues concluded.
 
In each case, there is an implication that the failure lies not with the drug(s), but rather with the gut microbes and even with the patient.
 
The problem was not that my mom could never get comfortable in her own home, but rather that the living room furniture conspired against her.
 
As an academic endeavor and as an industry, we struggle to accept that our efforts to develop novel treatments for various ailments will not work for everyone. It would have worked, we convince ourselves, if not for those meddling kids and their dog.
 
When we report clinical trials, for example, we often describe the patient population as subjects who failed previous courses of treatment. The patients failed the treatment. The treatment was blameless.
 
My worry is that the microbiome will suffer guilt by association. Rather than simply see the gut microbiota as one more factor informing treatment decisions, we will see it as a target to be controlled with yet another drug.
 
In an interview for my last Special Report on Cancer, Agilent’s David Ferrick spent a lot of time talking about the concept of metabolic equilibrium. The success of cancer, he implies, is its effectiveness at creating a new equilibrium that works in its favor.
 
From his perspective, the mutations we associate with cancer don’t drive the disease so much as help establish that new equilibrium.
 
Beyond tumor cells and microenvironment, however, he also sees a significant role for the microbiome in cancer and other diseases more broadly.
 
“If you believe my theories about metabolic equilibrium, for sure the microbiome has to be in equilibrium with the metabolic homeostasis,” he says, describing the system as a symbiosis.
 
I concur.
 
Our individual microbiomes are largely our living rooms, and it is vital to learn how to live with (and ideally, work with) the furniture we have, to look for the opportunities available rather than the inconveniences we imagine.
 
Precision medicine, if we dare use that term, was not intended to describe the nature of the therapeutic, but rather to describe its applicability and relevance to an individual.
 
The patient did not fail treatment. The gut microbe did not interfere with treatment.
 
Treatment was suboptimal, and care is a work in progress.

Randall C Willis can be reached by email at willis@ddn-news.com

References:
  • Lewis and Strandwitz. “Microbes make metabolic mischief by targeting drugs.” Nature. 2019 (http://doi.org/10.1038/d41586-019-01851-x)
  • Rekdal et al. “Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism.” Science. 2019 (https://doi.org/10.1126/science.aau6323)
  • Willis. “SPECIAL REPORT ON CANCER: Metabolic renaissance?” DDNews. June 2019 (http://ddn-news.com/index.php?pg=77&articleid=13372)
  • Zimmerman et al. “Mapping human microbiome drug metabolism by gut bacteria and genes.” Nature. 2019 (https://doi.org/10.1038/s41586-019-1291-3)
 

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