Crude proline modulates the microbiota-gut-brain axis by attenuating curli-associated α-synuclein accumulation and regulating Wnt/β-catenin signaling in Parkinson's disease.

This study investigated whether crude proline (CP), a metabolite fraction derived from heat-killed Enterococcus faecium (E. faecium) FBL1 isolated from makgeolli, is associated with the modulation of microbiota-host interactions within the microbiota-gut-brain axis and attenuation of PD-related pathology. CP was purified using fast protein liquid chromatography and liquid chromatography-mass spectrometry. Its biological effects were evaluated in SH-SY5Y and Caco-2 cell models and in an MPTP-induced mouse model of PD, followed by behavioral, microbiota, and molecular analyses. CP treatment significantly improved motor function and reduced CsgA-associated bacterial amyloid formation and α-synuclein accumulation in gut and brain tissues. Microbiota analysis indicated partial improvement of PD-associated dysbiosis, characterized by increased beneficial taxa (Lachnospiraceae and Ruminococcaceae) and reduced inflammation-associated taxa (Tannerellaceae and Muribaculaceae). These changes were accompanied by enhanced intestinal barrier integrity and regulation of MAPK and Wnt/β-catenin signaling pathways. CP attenuated curli-associated α-synuclein accumulation and alleviated inflammatory and apoptotic responses within the microbiota-gut-brain axis. CP derived from makgeolli-associated E. faecium FBL1 modulates microbiota-driven pathology and may represent a microbiota-targeted functional bioactive compound relevant to microbiota-gut-brain axis homeostasis. These findings further suggest the functional relevance of traditional fermented food systems.