Dynamic human gut microbiome and immune shifts during an immersive psychosocial intervention program

• We studied changes in gut microbiome, cytokines, and depression symptoms after a psychosocial intervention. • Prevotella -dominant enterotypes linked to higher well-being scores, suggesting potential mental health benefits. • Prevotella dominance showed lower levels of depression-related cytokines vs. Bacteroidetes or Ruminococcus dominance. • Depression altered stability in microbial families of Bacteroidaceae and Ruminococcaceae but not Prevotellaceae . • The immune system may mediate links between the gut microbiome and depression symptoms. Although depression is a leading cause of disability worldwide, the pathophysiological mechanisms underlying this disorder—particularly those involving the gut microbiome—are poorly understood. To investigate, we conducted a community-based observational study to explore complex associations between changes in the gut microbiome, cytokine levels, and depression symptoms in 51 participants ( M age = 49.56, SD = 13.31) receiving an immersive psychosocial intervention. A total of 142 multi-omics samples were collected from participants before, during, and three months after the nine-day inquiry-based stress reduction program. Results revealed that depression was associated with both an increased presence of putatively pathogenic bacteria and reduced microbial beta-diversity. Following the intervention, we observed reductions in neuroinflammatory cytokines and improvements in several mental health indicators. Interestingly, participants with a Prevotella -dominant microbiome showed milder symptoms when depressed, along with a more resilient microbiome and more favorable inflammatory cytokine profile, including reduced levels of CXCL-1. These findings reveal a potentially protective link between the Prevotella-dominant microbiome and depression, as evidenced by a reduced pro-inflammatory environment and fewer depressive symptoms. These insights, coupled with observed improvements in neuroinflammatory markers and mental health from the intervention, may highlight potential avenues for microbiome-targeted therapies for managing depression.