Sulfate reducing bacteria induce α-synuclein in intestinal and neuronal cells and tissues and inhibit tyrosine hydroxylase in neuronal cells.

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IntroductionParkinson's disease (PD), a synucleopathy characterized by the presence of α-synuclein (α-syn) aggregates in the brain, is thought to originate in the intestine. Desulfovibrio, resident gut sulfate reducing bacteria (SRB), usually found in very low numbers in a healthy gut, are found in higher numbers in PD. In a recent study, a separate group demonstrated that Desulfovibrio isolated from both PD patients and healthy subjects were fed to C. elegans and were found to increase α-syn aggregates in the head region of the worms. How these bacteria induce α-syn aggregates in the brain through the gut remain unknown. We tested whether Desulfovibrio induced α-syn aggregates in the intestinal cells and triggered α-syn secretion from these cells into the growth medium and whether this growth medium (devoid of bacteria) further induced α-syn aggregates in neurons. We also tested whether Desulfovibrio directly induced α-syn aggregates in neuronal cells and inhibited protein expression of tyrosine hydroxylase (TH), a key dopamine-producing enzyme. We also tested whether Desulfovibrio increased α-syn levels in intestine, plasma, and in brain in mice.MethodsEnteroendocrine STC-1 and neuronal SH-Sy5y cells were infected with Desulfovibrio vulgaris (DSV). We measured α-syn aggregation by immunofluorescence. α-syn levels in cell culture supernatant (sup), tissues, and plasma were measured by enzyme-linked immunosorbent assay (ELISA). Protein expression of TH and α-syn was analyzed by Western blot.ResultsWe found that DSV increased the number of STC-1cells with α-syn aggregates and also induced α-syn expression in these cells. Sup from DSV-infected STC-1 had higher α-syn levels compared to control uninfected sup and could induce α-syn aggregates in SH-Sy5y. DSV also directly induced a syn aggregates and inhibited TH in SH-Sy5y. DSV-gavaged mice had higher levels of α-syn in the duodenum, plasma, and in brain and also showed a decreasing trend in TH expression in the brain.ConclusionThus, our findings provide a gut-to-brain link tied to the ability of SRB in the gut-to increase expression, aggregation and spread of α-syn and decrease of TH in PD.

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