A prebiotic diet modulates microglial states and motor deficits in α-synuclein overexpressing mice

Abstract

Parkinson's disease (PD) is a movement disorder characterized by neuroinflammation, α-synuclein pathology, and neurodegeneration. Most cases of PD are non-hereditary, suggesting a strong role for environmental factors, and it has been speculated that disease may originate in peripheral tissues such as the gastrointestinal (GI) tract before affecting the brain. The gut microbiome is altered in PD and may impact motor and GI symptoms as indicated by animal studies, though mechanisms of gut-brain interactions remain incompletely defined. Intestinal bacteria ferment dietary fibers into short-chain fatty acids, with fecal levels of these molecules differing between PD and healthy controls and in mouse models. Among other effects, dietary microbial metabolites can modulate activation of microglia, brain-resident immune cells implicated in PD. We therefore investigated whether a fiber-rich diet influences microglial function in α-synuclein overexpressing (ASO) mice, a preclinical model with PD-like symptoms and pathology. Feeding a prebiotic high-fiber diet attenuates motor deficits and reduces α-synuclein aggregation in the substantia nigra of mice. Concomitantly, the gut microbiome of ASO mice adopts a profile correlated with health upon prebiotic treatment, which also reduces microglial activation. Single-cell RNA-seq analysis of microglia from the substantia nigra and striatum uncovers increased pro-inflammatory signaling and reduced homeostatic responses in ASO mice compared to wild-type counterparts on standard diets. However, prebiotic feeding reverses pathogenic microglial states in ASO mice and promotes expansion of protective disease-associated macrophage (DAM) subsets of microglia. Notably, depletion of microglia using a CSF1R inhibitor eliminates the beneficial effects of prebiotics by restoring motor deficits to ASO mice despite feeding a prebiotic diet. These studies uncover a novel microglia-dependent interaction between diet and motor symptoms in mice, findings that may have implications for neuroinflammation and PD.

Relationship Between Short-chain Fatty Acids and Parkinson’s Disease: A Review from Pathology to Clinic

“…In MPTP mice, oral administration of Bifidobacterium breve CCFM1067 protected the blood-brain and intestinal barriers from damage by improving intestinal microecology and increasing the synthesis of SCFAs [ 168 ]. In ASO mice, a prebiotic diet modulated the activation of microglia and motor deficits by altering gut microbiome composition and the content of SCFAs [ 97 ]. Synbiotics are compound preparations of probiotics and prebiotics, which can more effectively exert the physiological activity of probiotics.…”

“…Toxic models of PD, such as MPTP and 6-OHDA, have significant neuroinflammation but are effectively suppressed by supplementation with SCFAs [ 23 , 41 , 54 , 96 ]. A prebiotic diet effectively improved the symptoms and pathology of ASO mice by increasing the production of SCFAs to inhibit microglia activation and induce their conversion to a neuroprotective subtype [ 97 ]. Interestingly, this study found that the levels of SCFAs and their receptors were not increased in the brain and that histone acetylation levels were not significantly altered, consistent with the reports by Erny [ 30 ].…”

Interplay of human gastrointestinal microbiota metabolites: Short-chain fatty acids and their correlation with Parkinson’s disease

“…Furthermore, the downregulation of α-Syn aggregation by SCFAs can be achieved indirectly through the inhibition of oxidative stress and neuroinflammation. [115,119] In patients with PD, α-Syn is detected in both the CNS and the enteric nervous system (ENS). A team investigating the relationship between α-Syn in enteroendocrine cells and sodium butyrate found that sodium butyrate activates the expression of autophagy gene Atg5 while inhibiting the PI3K/ Akt/mTOR pathway to mediate the degradation of α-Syn.…”

Overview of the Gut Microbiome

“…For example, treatment of alpha-synuclein overexpressing mice with a prebiotic high-fiber diet remodels the gut microbiome and attenuates motor deficits, alpha-synuclein pathology, and neuroinflammation. 147 Other dietary changes, such as adherence to a Mediterranean diet, which is known to promote the growth of beneficial microbes, can also modulate neurological disease outcomes. For example, switching to a Mediterranean diet altered the gut microbiome composition of patients with mild cognitive impairment and improved AD biomarkers in their CSF.…”