Characterisation of Serotonin Metabolism in Post-viral ME/CFS and Post-infectious Animal Models

Dr. Helena Radbruch presented on the work of the SERIMM consortium, which is investigating serotonin and immune system dysregulation in ME/CFS, using samples from both patient cohorts and COVID-19 animal models. One of the models is a SARS-CoV-2 mouse model wherein mice get infected with an adapted virus, followed by observation and behavioural tests. In parallel, the group analyses tissue at different time points, with results still pending. Their work also includes a hamster model, in which hamsters are infected with human virus. Initial results from the hamster observations point to a reduction in activity following infection, which may be sex-dependent. Multi-organ analyses in animals are still ongoing at this point. On the side of patient data-based investigations, the group is looking into cerebrospinal fluid (CSF) of post-COVID patients with measurable cognitive dysfunction, analysing for any metabolic changes. By quantifying 30 metabolites in the CSF, the group is currently looking into serotonin pathways and the gut-brain-axis. Their research so far revealed that post-COVID patients have increased levels of trimethylamine-N-oxide (TMAO), a gut microbiome-derived metabolite, as well as an increased kynurenine-pathway similarly to inflammatory controls, including patients with multiple sclerosis. Contrarily, the tryptophan pathway was not found to be significantly altered in post-COVID patients. However, post-COVID patients showed reduced serotonin-tryptophan ratios, albeit no overall reduction of serotonin levels were measured in the CSF, which challenges the concept of a generalised peripheral or central nervous system serotonin deficiency in ME/CFS or post-COVID. These observations highlight the potential role of the gut-immune-metabolic interface and gut-brain axis. Additional analysis of the proteome derived from the CSF of patients hints at a very highly upregulated immune system and metabolism. Proteomic profiling of blood samples from a different cohort of ME/CFS patients points in the same direction, this time highlighting the role of natural killer (NK) cell function and molecules linked to mitochondrial and synaptic function. As a next step, the group aims to validate their findings from the human studies in their animal models. Yet another component of their work covers postmortem analysis of brain stem tissue. Donors were not ME/CFS patients but individual who deceased following SARS-CoV-2 infection, including patients with neurodegenerative disease. Importantly, no virus was detectable in the brain. Alterations that were identifiable concerned the endothelial and microglial cells, again pointing to changes in the innate immune system. While the group is also looking at, and still learning about, serotonin in connection with brain stem tissue and different anatomical regions of the brain, they also recently investigated muscle tissue obtained via biopsies from ME/CFS patients enrolled in the VADYS-ME study. Applying a deep learning model, they analysed fibre size distribution in the muscle. Investigations still on the horizon for SERIMM will look at different cell types by single nuclei RNA sequencing.