Study reveals how gut imbalance can lead to Parkinson’s disease

There is growing evidence that the gut microbiota can influence the development and progression of neurodegenerative disorders. Two studies recently published by Brazilian researchers not only reinforce this hypothesis but also describe the mechanism by which dysbiosis – as the imbalance between pathogenic and beneficial bacterial species in the intestine is called – may favor the onset of Parkinson’s disease.

The investigation was conducted with support from the Research Support Foundation of the state from Sao Paulo (Fapesp) by researchers linked to the National Biosciences Laboratory (LNBio), which is part of the complex of the National Center for Research in Energy and Materials (CNPEM), in Campinas. Part of the results was published in February, in the journal iScience. The second article was disclosed this month in the magazine Scientific Reports.

“Studies have shown that the diagnosis of Parkinson’s disease occurs late. And that the disorder can originate much earlier in the enteric nervous system [que controla a motilidade gastrointestinal]before advancing to the brain through the autonomic fibers”, says Matheus de Castro Fonsecaresearch coordinator.

In fact, several recent studies have consistently reported the existence of intestinal dysbiosis in patients with sporadic Parkinson’s (cases in which there is no genetic factor involved), reporting a greater abundance of the bacterial species. Akkermansia muciniphila in fecal samples from these patients when compared to the control group.

“It has recently been described that specific cells of the intestinal epithelium, called enteroendocrine cells, have many neuron-like properties, including the expression of the α-synuclein protein. [αSyn], whose aggregation is known to be related to Parkinson’s disease and other neurodegenerative diseases. Because they are in direct contact with the intestinal lumen – that is, the interior space of the intestines – and are connected by synapse with enteric neurons, enteroendocrine cells form a neural circuit between the gastrointestinal tract and the enteric nervous system, thus being a possible key player in the emergence of Parkinson’s disease in the intestine”, informs Fonseca, who is currently conducting postdoctoral research on the subject at the California Institute of Technology (Caltech), in the United States.

With this knowledge in mind, the CNPEM group sought to understand whether the products secreted by the bacterium Akkermansia muciniphila could initiate aggregation of α-synuclein in enteroendocrine cells. And if αSyn aggregated in these cells could then migrate to peripheral nerve endings of the enteric nervous system.

“We found that the proteins secreted by the bacteria, when cultivated in the absence of intestinal mucus, induce an overload in the intracellular calcium signaling of enteroendocrine cells. This puts stress on the mitochondria of these cells. [as organelas responsáveis pela produção de energia]; synthesis and release of reactive oxygen species [que em excesso danificam as estruturas intracelulares]; and, then, aggregation of the αSyn protein”, says Fonseca.

“Furthermore, when we cultured enteroendocrine cells and neurons together, we saw that the aggregated αSyn protein can be transferred from one cell type to another,” he adds.

The finding is very important as it shows that intestinal dysbiosis can lead to an increase in bacterial species that eventually contribute to the aggregation of αSyn in the intestines. And that this protein can then migrate to the central nervous system, configuring a possible mechanism for the emergence of sporadic Parkinson’s disease.

“The cascade of reactions can start in the intestines and go up to the brain. People with a predisposition to sporadic Parkinson’s disease usually have, many years before, recurrent episodes of constipation. In our study with animal models, we found a direct correlation between intestinal dysbiosis and Parkinson’s”, comments Fonseca.

New prevention strategies

Studies on the microbiomes present in the human body are advancing rapidly. And there is a growing understanding of the correlation between imbalanced gut microbiota and neurodegenerative diseases – not just Parkinson’s, but Alzheimer’s and even autism. Dietary reviews, in order to rebalance the intestinal microbiota, and non-invasive transplantation of intestinal microbiota, through capsules, can be important resources to prevent these diseases.

“Neurodegenerative diseases still have no cure. Therefore, prevention is essential. Before, the focus of research was the brain. And, with decades of studies, not much progress has been made in this direction. Now we’re redirecting the focus, from the brain to the intestines. And the new findings look very promising. It is much easier to modulate the intestinal microbiota than to face an established and consolidated framework in the central nervous system”, emphasizes Fonseca.

The study received funding from Fapesp through a regular research aid and from one master’s scholarship. It also benefited from the use of the facilities and equipment of the National Institute of Photonics Applied to Cell Biology, based at the State University of Campinas (Unicamp) and sponsored by FAPESP and by the National Council for Scientific and Technological Development (CNPq).

The two studies published by Fonseca’s group are open access and can be consulted online.

The article Transcellular propagation of fibrillar α-synuclein from enteroendocrine to neuronal cells requires cell-to-cell contact and is Rab35-dependent is accessible at: www.nature.com/articles/s41598-022-08076-5.

the study Akkermansia muciniphila induces mitochondrial calcium overload and α-synuclein aggregation in an enteroendocrine cell line can be found at: www.cell.com/iscience/fulltext/S2589-0042(22)00178-X?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS258900422200178X%3Fshowall%3Dtrue.

This text was originally published by Agência FAPESP according to the Creative Commons CC-BY-NC-ND license. read the original here.

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