Gut microbiota relieves inflammation in the substantia nigra of chronic Parkinson's disease by protecting the function of dopamine neurons

Abstract

The composition of the intestinal flora of patients with Parkinson's disease (PD) can change. However, whether reshaping the gut microbial composition can treat PD remains to be seen. The present study evaluated the effect of intestinal flora in the treatment of PD in a C57BL/6 mouse PD model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Chronic, low-dose, MPTP-treated mice exhibited upregulated gene expression levels of TNF-α and IL-1β in the substantia nigra (SN) of the mice, and induced intestinal microbial disorders. This indicated that the chronic low-dose MPTP model could be used to evaluate the progress of early intestinal pathology and intestinal flora imbalance in PD. After transplantation of faecal bacteria to MPTP-induced PD mice, the level of inflammation in the SN of the mice was reduced, and motor dysfunction was alleviated. Notably, faecal microbiota transplantation (FMT) upregulated the abundance of Blautia but downregulated Anaerostipes , Bifidobacterium , ASF356 and Ruminococcus in the gut of PD mice. In addition, FMT reduced the activation of microglia and astrocytes in the SN and reduced the expression levels of GSK3β, IL-1β, inducible nitric oxide synthase and phosphorylated PTEN in the SN. Overall, the present study demonstrated that gut microbial dysfunction is associated with the pathogenesis of PD, and that FMT can protect PD mice by inhibiting neuroinflammation.

The Interplay between Gut Microbiota and Parkinson’s Disease: Implications on Diagnosis and Treatment

“…Following the successful use of FMT in the treatment of refractory or recurrent Clostridium difficile infection, several studies have been conducted to explore FMT as a therapeutic strategy for a wide range of neurological disorders, including multiple sclerosis, epilepsy, ASD, Tourette syndrome, diabetic neuropathy, AD and PD, with promising preclinical and clinical data [ 30 , 465 , 466 , 467 , 468 ]. Concerning PD, consistent preclinical studies and a handful of human case reports have shown that FMT might be exploited to reduce motor and non-motor symptoms, as well as constipation, at least in the short term [ 40 , 465 , 469 , 470 , 471 , 472 , 473 , 474 , 475 , 476 , 477 ] ( Table 4 ). Early evidence came in 2016 from the work of Sampson et al, who first reported that the transfer of fecal matter from human PD patients to α-synuclein overexpressing mice substantially worsened their physical symptoms in comparison with mice receiving feces from healthy human donors [ 40 ].…”

“…These results were then confirmed in 2018, when Sun et al showed that fecal microbiota transfer from PD mice to their healthy counterpart increases motor deficits while reducing the striatal levels of the neurotransmitters dopamine, serotonin and their metabolites, thus reproducing the typical features of the disease [ 469 ]. Conversely, fecal matter transplantation from healthy mice to PD recipient mice improved physical performance, ameliorated motor symptoms and reduced dysbiosis in several independent studies [ 469 , 470 , 471 , 472 ]. Looking at the GM composition, there is evidence that FMT re-establishes eubiosis by disadvantaging the growth of Desulfovibrio , Akkermansia and Proteobacteria (orders Enterobacteriales and Turicibacteriales ), while simultaneously favoring the proliferation of beneficial bacteria such as Bacteroidetes and Actinobacteria phyla, with a particular effect on Blautia and Prevotella species [ 469 , 470 , 472 ].…”

“…Conversely, fecal matter transplantation from healthy mice to PD recipient mice improved physical performance, ameliorated motor symptoms and reduced dysbiosis in several independent studies [ 469 , 470 , 471 , 472 ]. Looking at the GM composition, there is evidence that FMT re-establishes eubiosis by disadvantaging the growth of Desulfovibrio , Akkermansia and Proteobacteria (orders Enterobacteriales and Turicibacteriales ), while simultaneously favoring the proliferation of beneficial bacteria such as Bacteroidetes and Actinobacteria phyla, with a particular effect on Blautia and Prevotella species [ 469 , 470 , 472 ]. Moreover, FMT appears to protect from gut inflammation by promoting intestinal barrier integrity and reducing the levels of LPS in the colon, serum, and SN, therefore preventing leaky gut and systemic inflammation [ 470 ].…”

“…At the brain level, FMT contrasts cognitive damage by decreasing α-synuclein expression and restoring the optimal levels of the striatal neurotransmitters dopamine and serotonin, thus supporting neuroprotection [ 469 , 471 , 473 ]. Notably, decreased neuroinflammation following FMT has been reported by numerous preclinical studies [ 469 , 470 , 471 , 472 ]. This beneficial effect should be ascribed to the ability of GM to modulate microglia and astrocyte activation in SN by regulating the TLR4/NF-κB pro-inflammatory pathway and reducing the expression of GSK3β, iNOS and IL-1β, which are implicated in PD pathogenesis and progression [ 469 , 470 , 471 , 472 , 478 , 479 , 480 ].…”

“…Notably, decreased neuroinflammation following FMT has been reported by numerous preclinical studies [ 469 , 470 , 471 , 472 ]. This beneficial effect should be ascribed to the ability of GM to modulate microglia and astrocyte activation in SN by regulating the TLR4/NF-κB pro-inflammatory pathway and reducing the expression of GSK3β, iNOS and IL-1β, which are implicated in PD pathogenesis and progression [ 469 , 470 , 471 , 472 , 478 , 479 , 480 ].…”