Exercise-Induced Myokines and Microbial Metabolites Mediate Muscle-Brain-Gut Axis Signaling, Influencing Neuroplasticity

Traditional exercise physiology often adopts an organ-centric view, overlooking the intricate molecular interplay between skeletal muscle, the brain, and the gut microbiome. This systemic understanding is crucial for optimizing human health and preventing chronic diseases, as these interactions profoundly influence performance and overall well-being. Current approaches often lack the integrated molecular insights needed to fully leverage exercise for therapeutic benefits. This review addresses this gap by synthesizing evidence on the genetic and molecular underpinnings of this critical triad, highlighting key mediators that can be targeted for intervention.

Researchers conducted a systematic review following PRISMA 2020 guidelines, searching PubMed, Embase, and Web of Science up to October 2023. They identified original research articles investigating at least two components of the muscle-brain-gut axis with molecular data. Exclusion criteria included non-English articles, conference abstracts, and studies lacking molecular insights. Evidence was categorized into Grades 1-4 based on methodological rigor, omics integration, reproducibility, and translational relevance to human physiology and disease models, aiming to synthesize a comprehensive molecular understanding.

The systematic review analyzed 154 studies, identifying a total of 987 molecular associations within the muscle-brain-gut axis. > Among these, 59 associations (Grades 1-2) presented robust evidence for genetically and functionally validated pathways. Key mediators included exercise-induced myokines such as irisin and BDNF, alongside microbially derived metabolites like short-chain fatty acids (SCFAs) and tryptophan derivatives. These mediators were found to significantly modulate critical physiological processes, including neuroplasticity, mitochondrial function, inflammation, and HPA axis activity. Furthermore, the review highlighted bidirectional signaling, where psychobiological factors influenced microbial composition. A substantial portion of the identified associations (n=952) were noted to have limitations due to methodological variability or insufficient mechanistic depth, underscoring the need for more rigorous research. The integration of multi-omics platforms (metagenomics, metabolomics, proteomics) was identified as a crucial tool for advancing personalized exercise interventions and biomarker discovery.