Early life adversity predicts brain-gut alterations associated with increased stress and mood

Abstract

Alterations in the brain-gut system have been implicated in various disease states, but little is known about how early-life adversity (ELA) impacts development and adult health as mediated by brain-gut interactions. We hypothesize that ELA disrupts components of the brain-gut system, thereby increasing susceptibility to disordered mood. In a sample of 128 healthy adult participants, a history of ELA and current stress, depression, and anxiety were assessed using validated questionnaires. Fecal metabolites were measured using liquid chromatography tandem mass spectrometry-based untargeted metabolomic profiling. Functional brain connectivity was evaluated by magnetic resonance imaging. Sparse partial least squares-discriminant analysis, controlling for sex, body mass index, age, and diet was used to predict brain-gut alterations as a function of ELA. ELA was correlated with four gut-regulated metabolites within the glutamate pathway (5-oxoproline, malate, urate, and glutamate gamma methyl ester) and alterations in functional brain connectivity within primarily sensorimotor, salience, and central executive networks. Integrated analyses revealed significant associations between these metabolites, functional brain connectivity, and scores for perceived stress, anxiety, and depression. This study reveals a novel association between a history of ELA, alterations in the brain-gut axis, and increased vulnerability to negative mood and stress. Results from the study raise the hypothesis that select gut-regulated metabolites may contribute to the adverse effects of critical period stress on neural development via pathways related to glutamatergic excitotoxicity and oxidative stress.

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“…Participants were excluded for the following: pregnant or lactating, substance use, abdominal surgery, tobacco dependence (half a pack or more daily), extreme strenuous exercise (>8 h of continuous exercise per week), current or past psychiatric illness and major medical or neurological conditions, similar to our previous study. 14 Participants taking medications that interfere with the central nervous system or regular use of analgesic drugs were excluded. 14 Because of the effect of handedness on brain signatures and brain function related to laterality, only right-handed participants were included to exclude this as a cofounder.…”

“… 14 Participants taking medications that interfere with the central nervous system or regular use of analgesic drugs were excluded. 14 Because of the effect of handedness on brain signatures and brain function related to laterality, only right-handed participants were included to exclude this as a cofounder. 15 Included participants were also required to not have taken antibiotics for at least 3 months before enrolling in the study, similar to previously published works.…”

“… 15 Included participants were also required to not have taken antibiotics for at least 3 months before enrolling in the study, similar to previously published works. 14 Since female sex hormones, such as estrogen are known to affect brain structure and function, we used females who were premenopausal and who were scanned during the follicular phase of their menstrual cycles as determined by self-report of their last day of the cycle. 14 Participants with hypertension, diabetes, metabolic syndrome or eating disorders were excluded to minimize confounding effects.…”

“… 14 Since female sex hormones, such as estrogen are known to affect brain structure and function, we used females who were premenopausal and who were scanned during the follicular phase of their menstrual cycles as determined by self-report of their last day of the cycle. 14 Participants with hypertension, diabetes, metabolic syndrome or eating disorders were excluded to minimize confounding effects. We used body mass index (BMI) cutoffs to define our groups: Individuals with BMI < 30 were normal, and BMI ≥ 30 were considered obese.…”

“…The Diet Checklist is a questionnaire developed by our institution and used in our previously published works. 14 It is intended to represent the diet that best reflects what participants consume on a regular basis. 14 The specific diets incorporated into this checklist are summarized in supplemental Table S1.…”