Healthy Human Fecal Microbiota Transplantation into Mice Attenuates MPTP-Induced Neurotoxicity via AMPK/SOD2 Pathway

Abstract

Increasing evidence has shown that gut dysbacteriosis may play a crucial role in neuroinflammation in Parkinson's disease (PD). However, the specific mechanisms that link gut microbiota to PD remain unexplored. Given the critical roles of blood-brain barrier (BBB) dysfunction and mitochondrial dysfunction in the development of PD, we aimed to evaluate the interactions among the gut microbiota, BBB, and mitochondrial resistance to oxidation and inflammation in PD. We investigated the effects of fecal microbiota transplantation (FMT) on the physiopathology of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. The aim was to explore the role of fecal microbiota from PD patients and healthy human controls in neuroinflammation, BBB components, and mitochondrial antioxidative capacity via the AMPK/SOD2 pathway. Compared to control mice, MPTP-treated mice exhibited elevated levels of Desulfovibrio, whereas mice given FMT from PD patients exhibited enriched levels of Akkermansia and mice given FMT from healthy humans showed no significant alterations in gut microbiota. Strikingly, FMT from PD patients to MPTP-treated mice significantly aggravated motor impairments, dopaminergic neurodegeneration, nigrostriatal glial activation and colonic inflammation, and inhibited the AMPK/SOD2 signaling pathway. However, FMT from healthy human controls greatly improved the aforementioned MPTP-caused effects. Surprisingly, the MPTP-treated mice displayed a significant loss in nigrostriatal pericytes, which was restored by FMT from healthy human controls. Our findings demonstrate that FMT from healthy human controls can correct gut dysbacteriosis and ameliorate neurodegeneration in the MPTP-induced PD mouse model by suppressing microgliosis and astrogliosis, ameliorating mitochondrial impairments via the AMPK/SOD2 pathway, and restoring the loss of nigrostriatal pericytes and BBB integrity. These findings raise the possibility that the alteration in the human gut microbiota may be a risk factor for PD and provide evidence for potential application of FMT in PD preclinical treatment.

Regulation of miRNA expression in the prefrontal cortex by fecal microbiota transplantation in anxiety-like mice

“…Akkermansia, a beneficial gut bacterium, has demonstrated the ability to regulate immune response, reduce intestinal inflammation, and show promise in alleviating mental illnesses. Importantly, direct supplementation of Akkermansia has been linked to increased growth of Bifidobacterium ( 31 ) and a reduction in depressive and anxious behavior after chronic stress ( 32 ), potentially through the restoration of dopamine and BDNF levels or the modulation of AMPK ( 33 ) and PI3K/AKT signaling pathways to inhibit neuroinflammation through CREB ( 34 ). Additionally, Bifidobacterium and Butyricimonas can enhance the production of butyrate, an anti-inflammatory substance that impedes the entry of intestinal toxins into the brain.…”

Curcumin regulates autophagy through SIRT3-SOD2-ROS signaling pathway to improve quadriceps femoris muscle atrophy in KOA rat model

“…We cut the PVDF membrane while retaining sufficient width and length to allow different positions of the PVDF membrane to bond with different primary antibodies. Then blotted with primary antibodies for LC3 (1:1000, ab192890, Abcam) 54 , P62 (1:1000, ab109012, Abcam) 55 , SIRT3 (1:500, #5490, CST) 56 , SOD2 (1:1000, #13141, CST) 57 , acetylated SOD2 (1:1000, ab137037, Abcam) 58 and GAPDH (1:2000, 60004-1-Ig, Proteintech) 59 overnight at 4 °C. Then, incubate with the secondary antibody for 1.5 h at room temperature.…”

Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases

“…524 A substantial body of literature has demonstrated the potential of microbiome-based therapeutics in alleviating dopaminergic damage and motor deficits in PD mouse models. 217,261,321,393,492,525,526 Adjunctive probiotic administration was found to increase serum dopamine levels and improve motor function in PD patients receiving conventional regimen, compared to patients receiving conventional regimen alone. 491 Moreover, the administration of berberine has been shown to stimulate the production of dopa and dopamine in the gut microbiota by activating tyrosine hydroxylase and dopa decarboxylase.…”

“…These effects are attributed to the reduction of glial activation, as well as the restoration of metabolite and neurotransmitter abnormalities. 217,[259][260][261] In addition, it was found that FMT from healthy human controls mitigated MPTP-induced dysbiosis and neurotoxicity in MPTPinduced mice, whereas FMT from PD patients exacerbated these pathologies. 261 Taken together, these findings corroborate the contributory roles of gut microbiota in driving glial activation and neuropathologies.…”