Artefactual source of 2-hydroxypyridine

Abstract

As part of the revisions of our original manuscript, we performed 13C-labelling experiments with cultures of the microorganism most strongly correlated with 2-hydroxypyridine (2-HP), i.e. the archaeal species Methanobrevibacter smithii. Although unlabelled 2-HP was detected in the cultures, the measurements by gas chromatography-mass spectrometry (GC-MS) indicated that M. smithii was not the direct source of 2-HP as labelled 2-HP was not measured. Further experiments involving a labelled solvent (deuterated pyridine) and faecal samples from our original study alongside the use of additional analytical platforms and measurements on human blood plasma and mouse brain tissues demonstrate that 2-HP is an artefact of the measurements by GC-MS. It is produced in a sample-specific manner during the derivatisation process for GC-MS by a so far unknown chemical reaction. Our correlative links between archaea (M. smithii) and 2-HP remain but, based on these most recent results, cannot be directly mechanistically linked. Apart from this central limitation of our original study, we have so far not uncovered any reasons which would draw into question the validity of our in vitro and in vivo results linking 2-HP to the observed molecular, behavioural and pathological hallmarks of Parkinson’s disease.

The evolving role of methanogenic archaea in mammalian microbiomes

“…Further, this compound is a key molecule in disease pathogenesis and may indicate a causal role of M. smithii in Parkinson’s Disease. However, recent additional analyses by indicated that M. smithii was not the direct source of 2-hydroxypyridine and, as such, further validation is required to determine if M. smithii can produce this compound in vivo ( Wilmes et al, 2023 ). Adults with asthma were also found to have a reduction in M. smithii compared to control subjects ( Wang et al, 2018 ).…”