Molecular systems biology approaches to investigate mechanisms of gut-brain communication in neurological diseases.

While the incidence of neurological disease is increasing worldwide, treatment remains mostly limited to symptom management. The gut-brain axis, which encompasses the communication routes between microbiota, gut, and brain, has emerged as a crucial area of investigation for identifying new preventive and therapeutic targets in neurological disease. Due to the inter-organ, systemic nature of the gut-brain axis, together with the multitude of biomolecules and microbial species involved, molecular systems biology approaches are required to accurately investigate the mechanisms of gut-brain communication. High-throughput omics profiling, together with computational methodologies such as dimensionality reduction or clustering, machine learning, network inference and genome-scale metabolic models, allow to discover novel biomarkers and elucidate mechanistic insights. In this review, we introduce the general concepts of experimental and computational methodologies for gut-brain axis research and discuss their applications, mainly in human cohorts. We further highlight important aspects concerning rational study design, sampling procedures and data modalities relevant for gut-brain communication, strengths and limitations of methodological approaches and some future perspectives. In conclusion, we review how multi-omics analysis, together with advanced data mining, are essential to functionally characterize the gut-brain axis in neurological disease and finally put forward novel preventive or therapeutic strategies.