Abstract Introduction Regular exercise or physical activity can significantly modulate interactions in the gut-brain axis. Currently, it is hypothesized that this may influence the regulation of the serotonergic system and increase the synthesis and bioavailability of serotonin. However, this relationship, as well as the possible mechanisms, remains insufficiently explored. Objective This review aims to synthesize current evidence on the relationship between physical activity and exercise and their influence on gut microbiota composition and serotonin metabolism, and to analyze how these interactions may impact metabolic and psychological health. Methods The protocol is prepared following the preferred reporting items for systematic reviews and meta-analyses (PRISMA-P) guidelines. We will perform a systematic review of literature published between January 2016 and July 2024, using the databases PubMed, Google Scholar. In addition, manual searches will be carried out through related articles, and references to included articles. The main findings, including primary and secondary outcome measures, will be extracted from all eligible studies using a standardized instrument. Two authors will independently screen titles and abstracts, review full texts, and collect data. Disagreements will be resolved by discussion, and a third reviewer will decide if there is no consensus. We will synthesize the results using a narrative or a meta-analytic approach, depending on the heterogeneity of the studies. Expected results It is expected that this systematic review will provide a comprehensive and up-to-date overview of the current understanding of the relationship between exercise, gut microbiota, and serotonin metabolism. Furthermore, the study will identify potential gaps in knowledge that warrant further investigation through future research. Conclusions Here, we present the protocol for a systematic review that will consider all existing evidence from peer-reviewed sources relevant to the primary and secondary outcomes related to the relationship between exercise, gut microbiota, and serotonin metabolism. Systematic review registry This study was registered at the International Prospective Registry for Systematic Reviews (PROSPERO registration number: CRD42024606591). Keywords: Physical activity, Exercise, Gut microbiota, Gut-brain axis, Serotonin metabolism, Inflammation.  

The authors have declared no competing interest.

No funding was received for the development of this protocol.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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All data from this study will be made available in the online databases upon study completion.