Mental Health Symptom Reduction Using Digital Therapeutics Care Informed by Genomic SNPs and Gut Microbiome Signatures

Background: Mental health diseases are a major component of morbidity and health care costs. Obesity and gut disorders are comorbid with mental health, with the gut microbiome hypothesized to play a key mechanistic role in linking them. Pharmacological and behavioral interventions are currently used to treat mental health disorders, but they have limited efficacy. Dietary and weight-loss interventions have been shown to provide different benefits. Still, there exists conflicting evidence regarding their effects which may be due to an individual's genetic or microbiome factors modulating the improvement of symptoms. Objective: We aimed to identify genetic and gut microbiome factors that explain the improvement in mental health after a dietary and lifestyle intervention for weight loss. Methods: We recruited 369 individuals participating in the Digbi Health personalized digital care program, for which we evaluated the association between 23 genetic scores, the abundance of 178 gut microbiome genera, and 42 gut-brain modules (pathways related to neuroactive metabolites produced by gut microbes) with the presence/absence of anxiety/depression or sleep problems at baseline and improvement on anxiety, depression, and insomnia after losing at least 2% body weight. Results: The mean BMI and age of the study cohort were 34.6 and 48.7, respectively, and there was an overrepresentation of individuals with functional gastrointestinal disorders (84%). On average, the individuals lost 5.4% of body weight at the time of follow-up (mean of 88 days), and more than 95% reported improvement in at least one outcome. We found significant correlations between genetic scores with anxiety and depression at baseline, gut microbial functions with sleep problems at baseline, and genetic scores and gut microbial taxa and functions with anxiety, depression, and insomnia improvement. Among the gut microbial functions identified, the abundance of butyrate synthesis genes was associated with less than average improvement in depression symptoms, the abundance of kynurenine synthesis genes was associated with less than average improvement in anxiety symptoms, and the abundance of genes able to synthesize and degrade neuroactive hormones like nitric oxide was associated with greater than average improvement in depression and insomnia symptoms. Among the genetic scores identified, anxiety or depression at baseline were associated with genetic scores for alcohol use disorder and major depressive disorder, and greater than average improvement in anxiety and depression symptoms was associated with an obstructive sleep apnea genetic score. Furthermore, a type 1 diabetes genetic score was associated with a greater than average improvement of insomnia symptoms, whereas a type 2 diabetes genetic score was associated with a less than average improvement of insomnia symptoms. We compared the relative ability of demographic, genetic, and microbiome factors to explain baseline and improvement in mental health and found that genetic and microbiome factors provide value above demographic variables alone. Medication and recreational drug use do not confound microbiome associations with mental health. Conclusions: The digital therapeutics care program significantly decreased body weight and concomitantly decreased self-reported mental health symptom intensity. Our results provide evidence that genetic and gut microbiome factors help explain interindividual differences in mental health improvement after dietary and lifestyle interventions for weight loss. Thus, individual genetic and gut microbiome factors provide a basis for designing and further personalizing dietary interventions to improve mental health.