Enterococcus faecium activates BMP/SMAD-mediated osteoblastogenesis and Wnt mediated neurogenesis while inhibiting PD

Parkinson's disease (PD) is defined by neurodegeneration, muscle atrophy, and bone deterioration, largely due to dopamine depletion. This study evaluates the therapeutic potential of heat-killed Enterococcus faecium FBL1 (HEF) in mitigating PD-related dysfunction through osteoblastogenesis and neurogenesis pathways. In the rotarod test, MPTP-treated mice exhibited a significant reduction in walking time, 4.1 times lower than that of the normal group. However, treatment with HDF notably improved the retention time, with a dose-dependent increase, compared to MPTP group. Wire-hanging test showed enhanced muscle strength, as HEF-treated mice demonstrated a 2.1- and 3.3-fold increase in the latency to fall at low and high doses, respectively, when compared to MPTP group. Grip strength and forced swim test, further supported the findings of neuromuscular recovery and reduced immobility in the HEF treated mice. The alpha-synuclein aggregation in the brain and muscle induced by MPTP were attenuated by HEF. Volcano plot analysis of muscle tissue revealed that MPTP treatment caused significant dysregulation, with 142 upregulated and 163 downregulated genes, including the downregulation of Wnt signaling-related genes Astn1 and Frat2, which are involved in neurogenesis and muscle regeneration. Conversely, the osteogenesis-related gene Pbx1 was upregulated by HEF, compared to MPTP treated group. Treatment with HEF also restored gene expression, notably increasing Tnxb, essential for tissue integrity, and Gsn, involved in various biological processes, compared with MPTP. Key markers of skeletal muscle differentiation (Myf5, MyoG, Myh1), osteoblastogenesis (Bmp2, Bmp4, SMAD1/5/8, RUNX2), and neurogenesis (Wnt3a, Beta-catenin, TCF1, LEF1) were downregulated in MPTP-induced PD but restored by HEF. Inflammatory markers (TNF-alpha, iNOS, and NF-kappaB) were significantly elevated in the MPTP group. However, these levels were reduced by HEF in a dose-dependently. This study highlights the pivotal role of osteoblastogenic (BMP/SMAD signaling) and neurogenic (Wnt signaling) pathways in maintaining muscle and bone homeostasis in PD. HEF offers a novel therapeutic approach targeting the BMP/SMAD and Wnt signaling pathways to mitigate muscle and bone degeneration in patients with PD.