Oral Trehalose Intake Modulates the Microbiota–Gut–Brain Axis and Is Neuroprotective in a Synucleinopathy Mouse Model

Parkinson's disease (PD) is a neurodegenerative disease affecting dopaminergic neurons in the nigrostriatal and gastrointestinal tracts, causing both motor and non-motor symptoms. This study examined the neuroprotective effects of trehalose. This sugar is confined in the gut due to the absence of transporters, so we hypothesized that trehalose might exert neuroprotective effects on PD through its action on the gut microbiota. We used a transgenic mouse model of PD (PrP-A53T G2-3) overexpressing human α-synuclein and developing GI dysfunctions. Mice were given water with trehalose, maltose, or sucrose (2% <i>w</i>/<i>v</i>) for 6.5 m. Trehalose administration prevented a reduction in tyrosine hydroxylase immunoreactivity in the substantia nigra (-25%), striatum (-38%), and gut (-18%) in PrP-A53T mice. It also modulated the gut microbiota, reducing the loss of diversity seen in PrP-A53T mice and promoting bacteria negatively correlated with PD in patients. Additionally, trehalose treatment increased the intestinal secretion of glucagon-like peptide 1 (GLP-1) by 29%. Maltose and sucrose, which break down into glucose, did not show neuroprotective effects, suggesting glucose is not involved in trehalose-mediated neuroprotection. Since trehalose is unlikely to cross the intestinal barrier at the given dose, the results suggest its effects are mediated indirectly through the gut microbiota and GLP-1.