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The bidirectional microbiota–gut–brain axis has raised increasing interest over the past years in the context of health and disease, but there is a lack of information on molecular mechanisms underlying this connection. We hypothesized that change in microbiota composition may affect brain epigenetics leading to long-lasting effects on specific brain gene regulation. To test this hypothesis, we used  Zebrafish  (Danio Rerio) as a model system. As previously shown, treatment with high doses of probiotics can modulate behavior in  Zebrafish , causing significant changes in the expression of some brain-relevant genes, such as  BDNF  and  Tph1A . Using an ultra-deep targeted analysis, we investigated the methylation state of the  BDNF  and  Tph1A  promoter region in the brain and gut of probiotic-treated and untreated  Zebrafishes.  Thanks to the high resolution power of our analysis, we evaluated cell-to-cell methylation differences. At this resolution level, we found slight DNA methylation changes in probiotic-treated samples, likely related to a subgroup of brain and gut cells, and that specific DNA methylation signatures significantly correlated with specific behavioral scores.

DNA Methylation Profiles of Tph1A and BDNF in Gut and Brain of L. Rhamnosus-Treated Zebrafish