Neurotransmitter-producing commensal bacteria at the interface of host metabolism

Introduction. Trace amines (TAs) are neuro-monoamines produced by bacteria and humans mainly by decarboxylation of aromatic amino acids (AAAs). Bacterial AAA decarboxylases (AADCs) are generally specific in substrate preference. Staphylococcal AADC (SadA) is, however, non-specific and decarboxylates tryptophan, tyrosine and phenylalanine to tryptamine, tyramine, and phenethylamine, respectively. It is also able to convert dihydroxy phenylalanine and 5-hydroxytryptophan to dopamine and serotonin. Goals. What are the potential interactions between TA-producing commensal bacteria and the host cells? Materials & methods. The skin microbiome of healthy subjects was examined using shotgun metagenomic and culture-based analyses. The investigation of bacterial adherence and internalization was carried out using the HT-29 cell line. The in vitro and in vivo effects of TAs and TA-producing bacteria on wound healing assays were evaluated in HaCaT cells and in murine model. Results. Metagenomic analysis of the skin microbiota revealed a wide distribution of SadA homologs among at least 7 different phyla, remarkably within the Firmicutes phylum. In culture-based analysis, the AADC activity was found in isolates other than Staphylococcus sp. including Cutibacterium acnes, Corynebacterium sp., and Bacillus sp.. Staphylococcus epidermidis and S. pseudintermedius secrete TAs which trigger their adherence and internalization into human cells by activation of the α2-adrenergic receptor (AR). TAs could accelerate wound healing by antagonizing the b2-AR in keratinocytes which was confirmed in vivo by an application on the wound bed of TAs or a TA-producing S. epidermidis strain. As TAs can activate the wide distributed TA-associated receptors (TAARs) at nanomolar affinities, it is not unexpected to have their wide-range presynaptic "amphetamine-like" effects all over body and brain which we are currently investigating using Parkinson"s and Alzheimer"s mouse models. Conclusion. TA-producing bacteria are ubiquitous in human microbiota which interact with host metabolism through direct stimulation of TAARs. Further studies are required to address more aspects of this interaction.