Enteric neurons appear to play a key role in the development of Parkinson’s disease


Researchers at Karolinska Institutet in Sweden and the University of North Carolina in the USA have mapped out the cell types behind various brain disorders.

The findings are published in Nature Genetics and offer a roadmap for the development of new therapies to target neurological and psychiatric disorders.

One interesting finding was that cells from the gut’s nervous system are involved in Parkinson’s disease, indicating that the disease may start there.

The nervous system is composed of hundreds of different cell types with very different functions. It is vital to understand which cell types are affected in each disorder so as to understand the causes of the disorders and, ultimately, develop new treatments.

Researchers have now combined mice gene expression studies with human genetics to systematically map cell types underlying various brain disorders, including Parkinson’s disease, a neurodegenerative disorder with cognitive and motor symptoms resulting from the loss of dopamine-producing cells in a specific region of the brain.

“As expected, we found that dopaminergic neurons were associated with Parkinson’s disease. More surprisingly, we found that enteric neurons also seem to play an important role in the disorder, supporting the hypothesis that Parkinson’s disease starts in the gut,” says one of the study’s main authors Patrick Sullivan, Professor at the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet and Yeargan Distinguished Professor at the University of North Carolina.

When the researchers analysed differences in brain tissue from healthy individuals and people with Parkinson’s disease at different stages of the disease, they made another unexpected discovery. A type of support cell in the brain called oligodendrocytes were found to be affected early on, suggesting that they play a key role in the early stages of the disease.

“The fact that the animal studies pointed us to oligodendrocytes and that we were then able to show that these cells were also affected in patients suggests that the results may have clinical implications,” says Jens Hjerling-Leffler, research group leader at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet and the other main author of the study.

The oligodendrocytes appear to be affected even before the loss of dopaminergic neurons.

“This makes them an attractive target for therapeutic interventions in Parkinson’s disease,” says Julien Bryois, researcher at the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet and one of the first authors of the study.

The study was financed by the Swedish Research Council, StratNeuro, the Wellcome Trust, the Swedish Brain Foundation, the Swiss National Science Foundation, the US National Institute of Mental Health, and the Psychiatric Genomics Consortium.

Patrick Sullivan reports that he is currently a member of the pharmaceutical company Lundbeck’s advisory committee and that he has received grants from them. For the past three years he has been a member of Pfizer’s scientific advisory board and received fees from Element Genomics and Roche.

Co-author Cynthia Bulik has received grants from Shire and is a member of their scientific advisory board. She is also an author and recipient of royalties from both Pearson and Walker.

The Gut-Brain Axis and Parkinson’s Disease

The gut-brain axis is mediated by intense bidirectional communication between the CNS and the ENS (63). Through the ENS, the gut microbiota influences the development and function of all divisions of the nervous system (64) and this association was established very early during the evolution of multicellular organisms.

The first nervous system appeared more than 500 million years ago before the divergence of cnidarians and bilaterians, the two metazoan sister groups (65). That primitive brain had a simple structure, organized as a diffuse nerve net which controlled a restricted set of basic behaviors and was the template for the subsequent evolution of the mammalian ENS (66–68), which retained many of its basic structural characteristics, such as a network of nervous ganglia distributed in the myenteric and submucous plexuses (69).

Higher vertebrates went to evolve an additional set of neural structures in the central nervous system (CNS), tasked with the control of more sophisticated behaviors (70).

However, the ENS and the CNS maintain intense crosstalk through reciprocal connections mediated by the VN (Figure 1) and pelvic nerve in mammals (71, 72). As the main substrate for this information exchange, the vagus nerve is an attractive target of neurostimulation therapies for the treatment of psychiatric and gastrointestinal disorders (73, 74).

The GI tract harbors a complex microbial ecosystem (Figure 1), consisting of bacteria, archaea, protists, and eukaryotic and prokaryotic viruses, also known as bacteriophages (75–77).

The human microbiome has coevolved with its host (78), which keeps a tight leash on the intrinsic competitive nature of the microorganisms that comprise the microbiome, through both the nervous (71, 79, 80) and the immune systems (81, 82).

This arrangement maximizes the benefits the host gains from the symbiotic relationship, including protection against pathogens, improved nutrition, and mental health (81). A sub-type of intestinal epithelial cells called enteroendocrine cells, provide a signaling pathway through which the microbiome interacts with the CNS via the vagus nerve (20, 83).

Enteroendocrine cells have diverse phenotypes and express a variety of peptides/hormones that can act as signaling molecules on distinct targets, both local and distant, and some are chemoreceptors responding to a variety of luminal stimuli (84, 85).

As other intestinal epithelial cells, enteroendocrine cells express toll-like receptors (86), allowing them to detect bacterial products, and activate vagal afferents through basal processes called neuropods (see Figure 1) (20, 87).

The Gut Microbiome and Brain Function

There is increasing evidence of the association between microbiome dysfunction and CNS-related co-morbidities, such as anxiety, depression, autism spectrum disorders, Alzheimer’s disease and PD (88–92).

This association probably arose as a by-product of natural selection forces acting on microorganisms to adapt to the host and vice-versa (93). The effect of the microbiota on the CNS can lead to behavior modifications (93–95) and even to host manipulation (96) associated with increasing fitness of its bacterial populations.

For instance, the microbiome can influence social interactions by acting on the nutritional behavior of individual animals, particularly those from social species where individuals share microbes and interact around foods (97).

The proximate neuro-endocrinological and inflammatory mechanisms underlying this type of host manipulation are largely shared by the microbiome and the host (98, 99). For instance, levels of many neurotransmitters that are important for the expression of social behavior, such as serotonin (5-HT), dopamine, norepinephrine (NE), γ-aminobutyric acid (GABA), and glutamate are either expressed or regulated by bacteria (100–102).

Particularly, most of the body’s serotonin (5-HT) (5-hydroxytryptamine) is produced in the gut by enterochromaffin cells (EC) under the influence of the microbiome (103). The activation of 5-HT4 receptors induces the maturation of the ENS and regulates its adult function (104).

In the gut, there are three major metabolic pathways leading from the essential amino acid tryptophan (Trp) to 5-HT, kynurenine (Kyn), and indole derivatives, which are under the direct or indirect control of the microbiota (105).

During inflammatory states, most tryptophan is diverted to the production of Kyn and its metabolites kynurenine acid (KYNA) and quinolinic acid (QUIN) (106). While KYNA is considered neuroprotective, QUIN can cause excitotoxicity as an agonist of N-methyl-d-aspartate (NMDA) receptor and contribute to the neuropathogenesis of PD [for review, see (107)].

Although α-syn aggregates are also seen in the ENS of normally aging subjects (108), especially in the appendix (109), it is more prevalent in PD patients (110). Recent in vivo models showed that accumulation of α-syn aggregates in the ENS can be induced by alterations in the gut microbiome (111).

Interestingly, Sampson et al. (112) demonstrated in mice, genetically modified to overexpress α-syn, that the presence of gut microbiota is necessary to promote pathological alterations and motor deficits similar to PD.

They also demonstrated that fecal transplants from PD patients impair motor function in the same mouse strain, strongly suggesting that gut microbes may play a pivotal role in the onset of synucleinopathies such as PD (112).

Underlying these findings is the fact that microbial amyloids produced by some members of the gut microbiota can be released in the extracellular space, where they can be internalized by neighboring cells, including neurons, and seed the formation of pathological aggregates of endogenous α-syn through permissive templating (113, 114).

The failure of normal clearance mechanisms such as the ubiquitin-proteasome system, characteristic of both familial and idiopathic PD (115), to degrade the misfolded protein, may facilitate the seeding process.

The concept of microbial dysbiosis also comprises the bacteriophage components of the microbiome (116). Bacteriophages (phages) are viral parasites of bacteria and are important regulators of host-microbiome interactions through horizontal gene transfer and antagonistic coevolution (117, 118).

Besides targeting bacteria, phages can impact human health by playing a direct role on intestinal inflammatory processes (119) and possibly causing α-syn misfolding (120). A recent study showed significant differences in the gut phagobiota of PD patients and healthy individuals and a depletion of Lactococcus bacteria (121) in the former, which is associated with the regulation of gut permeability (122) and dopamine production (102), two factors linked with the early signs of PD in the gut (123).

Phage therapy has recently returned to the spotlight as an alternative antimicrobial strategy (124, 125). Eventually, it may also contribute to fighting PD through targeted approaches to manipulate the microbiome (121).

Probiotic bacteria have been linked to improved GI symptoms associated with PD (126). Probiotics affect the functionality of the CNS through beneficial interactions with the commensal gut microbiota and modulation of gut-derived inflammation (127).

The microbiota of PD patients exhibits a pro-inflammatory profile (128, 129) due to increased intestinal permeability to endotoxins (lipopolysaccharide) (130). Bacterial amyloids may also favor a pro-inflammatory environment in the gut (131).

A common bacterial component, the Curli fimbriae, share structural and biophysical properties with amyloids and are produced by E. coli through coordinated biosynthetic processes (132).

Other components of the gut microbiome are also known to produce functional extracellular amyloids [e.g., Salmonella, Klebsiella, Citrobacter, and Bacillus species; (133)]. Since probiotic treatment induces an anti-inflammatory peripheral immune response in multiple sclerosis patients (134) there is a possibility they may also be beneficial for PD patients, although there are no reports corroborating this hypothesis.

One option is to take advantage of Lactobacilli’s ability to inhibit the formation of biofilms by pathogenic bacteria (135, 136). One caveat, however, is that the effects of probiotics are highly variable, being person-specific, as shown in a recent study (137).

This limitation may be counteracted with the use of genetically-modified probiotics able to deliver novel therapeutics efficiently and with site specificity (138). Despite the increasing number of probiotic products available to consumers and the aggressive marketing proclaiming their efficacy, there have been few studies addressing concerns about efficacy and, more importantly, the safety of these products (139).

There is an urgent need for more studies about the therapeutic potential of specific bacterial strains to help maintain oxidative and protein homeostasis in the ENS.

Concluding Remarks

Aging is the main risk factor for the development of PD (140) and delaying the aging process is neuroprotective to PD in animal models (141). Aging is also associated with the accumulation of neuroinflammatory sequelae and the breakdown of homeostatic mechanisms that protect against protein misfolding, oxidative stress, decreased mitochondrial function, etc.

The gut, as one of the main gateways to environmental exposure to the brain, may contribute to increasing the susceptibility to these factors. The microbiome has a protective effect mediating this exposure, and dysbiosis seems to be a pivotal risk factor for PD and other neurological disorders.

Thus, the adoption of preventive measures to ensure a healthy microbiome throughout the lifetime can potentially decrease the risk of developing PD and other neurodegenerative diseases. The widespread use of antibiotics, for instance, which can kill gut bacteria indiscriminately, can cause a shift of the microbiome to an alternative stable state with unknown consequences in the long term (142).

Karolinska Institute


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