Schizophrenia-associated gut microbiota are linked to reduced colonic PRODH expression and behavioral changes in mice

Schizophrenia (SCZ) is a chronic neuropsychiatric disorder whose biological basis remains incompletely understood. Growing evidence implicates the gut-brain axis in SCZ, but the host pathways through which disease-associated microbiota may influence behavior remain unclear. Here, we examined whether the gut microbiota from patients with SCZ is associated with behavioral and metabolic alterations in male C57BL/6N mice. Fecal microbiota transplantation (FMT) from patients with SCZ was associated with impaired short-term recognition memory, reduced social novelty preference, and decreased prepulse inhibition in recipient mice. Transcriptomic profiling of colonic tissue identified reduced expression of Prodh, which encodes proline dehydrogenase (PRODH), together with elevated plasma proline levels. Comparative microbiome analyses identified a five-species candidate consortium associated with the SCZ donor microbiome - Escherichia fergusonii, Shigella sonnei, Morganella morganii, Citrobacter freundii, and Enterococcus faecalis. Oral administration of this five-species mixture (5-SM) was associated with similar behavioral changes, reduced colonic PRODH expression, and hyperprolinemia in mice. Together, these findings support a possible association between schizophrenia-associated changes in the gut microbiota, altered intestinal proline metabolism, and behavioral changes in mice.