The Parkinson’s drug entacapone disrupts gut microbiome homeostasis via iron sequestration
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Abstract
Increasing evidence shows that many human-targeted drugs alter the gut microbiome, leading to implications for host health. However, much less is known about the mechanisms by which drugs target the microbiome and how drugs affect microbial function. Here we combined quantitative microbiome profiling, long-read metagenomics, stable isotope probing and single cell chemical imaging to investigate the impact of two widely prescribed nervous system targeted drugs on the gut microbiome. Ex vivo supplementation of physiologically relevant concentrations of entacapone or loxapine succinate to faecal samples significantly impacted the abundance of up to one third of the microbial species present. Importantly, we demonstrate that the impact of these drugs on microbial metabolism is much more pronounced than their impact on abundances, with low concentrations of drugs reducing the activity, but not the abundance of key microbiome members like Bacteroides, Ruminococcus or Clostridium species. We further demonstrate that entacapone impacts the microbiome due to its ability to complex and deplete available iron, and that microbial growth can be rescued by replenishing levels of microbiota-accessible iron. Remarkably, entacapone-induced iron starvation selected for iron-scavenging organisms carrying antimicrobial resistance and virulence genes. Collectively, our study unveils the impact of two under-investigated drugs on whole microbiomes and identifies metal sequestration as a mechanism of drug-induced microbiome disturbance.
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As ENT-Hi samples showed a strong, Raman unspecific signal during SRS pump-probe detection, we explored the origin of this signal and concluded that this is a photothermal (PT) signal originating from entacapone bioaccumulation within microbial cells (Supporting Information Text).
I'm curious if you can share insight into how to design an SRS imaging experiment to allow for this type of unexpected observation of the time-dependent photothermal signal.
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In complex microbial communities, all metabolically active cells will incorporate deuterium (D) from D2O into their biomass during synthesis of new macromolecules34. The newly formed carbon-deuterium (C-D) bonds can then be used as a read-out of microbial activity. Detection and quantification of C-D levels in single microbial cells can be achieved using SRS, a method that efficiently excites the Raman active vibrational modes coherently with two synchronized ultrafast lasers
This seems like a comprehensive and sensitive readout of microbial activity. It might be worth defining SRS as Stimulated Raman Scattering as the reader could mistake it for Spontaneous Raman Scattering.
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However, many of the detected effects were drug-specific, with ENT-Hi decreasing and LOX-Hi increasing total abundances of the genera Anaerostipes, Fusicatenibacter, Ruminococcus torques group, Eubacterium hallii group, Erysipelotrichaceae group UG-003 and Roseburia.
These opposite effects on the same group of strains by each drug is quite interesting. I'm curious about your interpretation as to why the ENT-Hi community looks so similar to the inoculum at 6 h except for the increase in E. coli abundance. One might think there's no effect of ENT-Hi on the community, but something is changing relative to the inoculum to allow E. coli to grow.
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Major shifts in the microbial community composition, as determined by 16S rRNA gene amplicon sequencing analyses, were detected in response to ENT-Hi, LOX-Hi and LOX-Low treatments
Is the major shift for the LOX-Hi and LOX-Low treatments the reduction in Bacteroides that is present at 6h but stronger at 24h? If so, it might be useful to call that out specifically for the reader because the fact that Bacteroides is affected might catch their attention.
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