Bacteriophages targeting Enterococcus faecalis enhance the therapeutic efficacy of levodopa in an MPTP-induced Parkinson's disease mouse model with E. faecalis gut colonization.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Enterococcus faecalis*/drug effects ; Levodopa* ; Bacteriophages*/physiology ; Gastrointestinal Microbiome*/drug effects ; Disease Models, Animal*; Animals ; Mice ; Male ; Parkinson Disease/therapy ; Parkinson Disease/drug therapy ; Parkinson Disease/microbiology ; Mice, Inbred C57BL ; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/adverse effects ; Antiparkinson Agents/pharmacology ; Antiparkinson Agents/therapeutic use ; Phage Therapy/methods

Despite the intensive research on gut microbiome-associated diseases over the past 20 years, pharmacological methods for effectively eliminating pathobionts remain unsatisfactory. This study investigated the therapeutic potential of bacteriophages against Enterococcus faecalis, in which bacterial tyrosine decarboxylase (TDC) converts orally administered levodopa (L-DOPA) to dopamine, in an MPTP mouse model of Parkinson's disease (PD). E. faecalis bacteriophages PBEF62, PBEF66, and PBEF67 (4 × 10 ¹⁰ PFU total/200 µl/day), and E. faecalis cells (2 × 10 ⁹ CFU/200 µl/day) were orally administered at 2-h intervals before every MPTP (i.p.) and/or L-DOPA (p.o.) treatments for 13 days. The relative abundances of E. faecalis cells and bacteriophages in the feces peaked at 4 and 12 h after administration and gradually decreased by 12 and 48 h, respectively. While the administration of E. faecalis cells eliminated the beneficial effect of L-DOPA on MPTP-induced behavioral deficits, as assessed by cylinder and rotarod tests, the co-administration of bacteriophages with bacterial cells restored this effect. The modulating effects of L-DOPA, E. faecalis, and bacteriophages on PD behavior were closely associated with choline acetyltransferase expression levels in the striatum but not with tyrosine hydroxylase in the substantia nigra of each group. Recurrence and extinction of PD behaviors following treatment with E. faecalis and/or bacteriophages were also coincident with the dopamine levels in the blood and brain tissues of PD mice. The effectiveness of L-DOPA was restored after the three types of E. faecalis bacteriophages selectively eliminated E. faecalis cells, along with the TDC gene copies and transcripts responsible for converting L-DOPA to dopamine in the gastrointestinal tract. In conclusion, a combination of bacteriophages PBEF62, PBEF66, and PBEF67 targeting E. faecalis demonstrates potential as a valuable supplement to L-DOPA therapy for PD.
(© 2024. The Author(s).)

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Keywords: Enterococcus faecalis; Bacteriophage; Gut microbiome; L-DOPA; Parkinson’s disease

46627O600J (Levodopa)
9P21XSP91P (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine)
0 (Antiparkinson Agents)

Date Created: 20241031 Date Completed: 20241031 Latest Revision: 20241102

20241102

PMC11525634

10.1038/s41598-024-77038-w

39478137