A protocol for the Teen Bugs study: An integrative, multi-omics approach to understanding the role of the gut microbiome and mesocorticolimbic system in adolescent mental health following early adverse caregiving.

Caregiving-related early adversities (crEAs) are potent risk factors for the development of internalizing psychopathology (e.g., depression, anxiety). Alterations to the dopaminergic mesocorticolimbic system, which supports the construction of reward-related experiences, are commonly observed following crEA exposure and are thought to mediate this risk. Indeed, many internalizing disorders are characterized by disruptions in how reward-related information is represented and used to guide affective and motivational states. Critically, the effects of crEA on mesocorticolimbic functioning may be shaped by input from peripheral systems, such as the gut microbiome, though such bottom-up signaling has been markedly understudied in humans. The Teen Bugs study was thus developed to identify gut microbiome-dependent metabolic pathways linking crEA exposure to mesocorticolimbic functioning and internalizing symptoms in adolescents, a group that experiences a disproportionate incidence of psychopathology relative to other age groups and is underrepresented in the gut microbiome literature. Adolescents aged 12-15 years, with and without histories of crEA exposure, will be followed across three timepoints over five years. At each timepoint, participants will complete a semi-structured clinical interview, a reward-guided decision-making task, and self-report questionnaires assessing mental health, previous caregiving experiences, reward-related behaviors, as well as developmental and lifestyle factors. Participants will also undergo multimodal neuroimaging that leverages MRI-based proxy markers of dopaminergic neurobiology and provide stool and blood samples for metagenomic and metabolomic profiling, respectively. This integrative design has the potential to clarify developmentally salient mechanisms that may serve as novel therapeutic targets for youth most at risk of, or already experiencing, internalizing psychopathology.