A systematic review exploring the association between the human gut microbiota and brain connectivity in health and disease

1 A body of pre-clinical evidence shows how the gut microbiota influence brain functioning, including brain connectivity. A growing number of studies have investigated the association between the gut microbiota and brain connectivity in humans. Linking brain connectivity measures to the gut microbiota can provide important mechanistic insights into the bi-directional gut-brain communication. In this systematic review, we therefore synthesized the available literature assessing this association, evaluating the degree of consistency in microbiota-connectivity associations. Following the PRISMA guidelines, a PubMed search was conducted, including studies published up to September 1, 2022. We identified 16 studies that met the inclusion criteria. Several bacterial genera, including Prevotella , Bacteroides , Ruminococcus and Blautia were most consistently reported in association with brain connectivity. Additionally, the salience (specifically the insula and anterior cingulate cortex), default mode and frontoparietal networks were most frequently associated with the gut microbiota, both in terms of microbial diversity and composition. Altogether, based on our synthesis, there is evidence for an association between the gut microbiota and brain connectivity. However, the specificity of the signal is yet unclear as most findings were poorly replicated across studies. The current studies show substantial inter-study heterogeneity in methodology and reporting, limiting the robustness and reproducibility of the findings and emphasizing the need to harmonize methodological approaches. To enhance comparability and replicability, future research should focus on further standardizing processing pipelines and employ data-driven multivariate analysis strategy.