Gut Inflammation Linked to the Development of Parkinson Disease – Psychiatry Advisor

A Danish study of patients with inflammatory bowel disease (IBD) and Parkinson disease (PD) found that patients with IBD had a 22% increased risk of developing PD over patients without IBD. The study, published in Gut, examined all Danish residents aged 15 years or older from 1977 to 2014 in the largest and longest population-based study of links between enteric inflammation and PD.1

A growing body of research points to the role of the gut-brain axis in the development of PD, with inflammation, irritable bowel syndrome, leaky gut, and altered gut microbiota observed in the gut, often years before the onset of symptoms of PD.2 The disease is strongly associated with the accumulation of Lewy bodies, which are eosinophilic deposits that occur within cell cytoplasm and are composed of a misfolded protein, alpha-synuclein. Some research points to the gut as the origin of the misfolded protein, spreading via the vagus nerve into the brain.3 In one study, alpha-synuclein injected in the gut walls of rats migrated to the brain stem through the vagus nerve at a rate estimated to be from 5 to 10 mm per day, thus providing startling evidence of the gut-brain connection.4 In fact, Lewy pathology can be detected in the gut of patients with PD as many as 20 years before their diagnosis via motor symptoms.5 Moreover, increases in intestinal alpha-synuclein are also strongly correlated with changes in gut microbiota that lead to inflammation and elevated permeability of the gut barrier.6

The possibility that PD may originate in the gut is also supported by discoveries of close associations between PD and inflammatory markers, including tumor necrosis factor-alpha and interleukin 6, which are present in patients with ulcerative colitis, IBD, and Crohn disease.2

Patients with PD have a distinctive fecal microbiome, even when they have shared the same diet for decades with other members of their households without PD. In a study of patients who had received treatment for PD for more than a year, patients microflora contained decreased levels of Prevotella when compared with healthy control individuals in their own households. As patients PD progressed, their levels of Prevotella markedly decreased.7 A genus of Gram-negative bacteria, Prevotella assists in the breakdown of complex carbohydrates, supplying the gut and body with short chain fatty acids (SCFAs), thiamine, and folate. Decreased numbers of Prevotella thus deprive the gut of important micronutrients, as a result reducing the production of essential vitamins and impairing secretions of gut hormones. Even reductions in only Prevotella, a single genus among the many microbiota that show distinctive changes in PD, can raise levels of inflammation in the gut, potentially affecting the central nervous system via the gut-brain axis.8,9

SCFAs may also play a role in the development and progression of PD. SCFAs are essential energy sources for colonocytes, the authors of a study published in Genome Medicine report, and reduced levels of SCFAs might not only contribute to a decreased colonic motility (i.e. constipation) but also led to an increase in intestinal barrier leakiness.10

In one recent study of a mouse model of PD, an impaired intestinal barrier and changes in gut microbiota resulted in distinctive alterations in the gut and brain alike.11 The intestinal barrier became hyperpermeable, and levels of anti-inflammatory bacteria, including Lactobacillus, decreased, whereas alpha-synuclein protein levels in the gut increased. These changes correlated with alterations in the brain consistent with progressive PD, including phagocytic microglial cells and decreased dopamine in the substantia nigra.11

Increasingly, researchers recognize the important role of environmental toxins in the development of PD and the gut as the gateway for exposures that reach the brain. To date, rotenone is the toxin most frequently linked to the development of PD, with researchers often using it to induce PD in mouse models of the disease.11,12 Widely deployed as a pesticide and insecticide, rotenone can be spread to selectively kill invasive fish species.13,14 Despite a 2011 study linking pesticides containing rotenone and paraquat to increased incidence rates of PD in farm workers,14 rotenone is only gradually being phased out in North America.13 In humans, the microbiome can mediate these exposures and protect the brain, making an unhealthy gut microbiome a pivotal risk factor for PD.15

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, report the authors of a recent study published in Frontiers in Neurology.15 These preventive measures include reducing the widespread use of antibiotics, which can kill gut microflora indiscriminately. In addition, adults can benefit from increasing their dietary fiber intake throughout life, as higher fiber intake also bolsters levels of Prevotella in the gut, where the bacteria play a key role in breaking down dietary fiber and complex carbohydrates.8

For clinicians, functional gastrointestinal disorders (FGIDs) can provide early warning signs of PD decades before the onset of symptoms, enabling both clinicians and patients to help mitigate the progression and severity of the disease in its early stages. During the early stages of PD, patients experience gastrointestinal dysmotility, including dysphagia, delayed gastric emptying, and bowel dysmotility. These symptoms may seem unremarkable to patients, who usually fail to report them unless clinicians specifically question them about certain symptoms, including early satiety, nausea, bloating, pain, and constipation. 16,17

The gut-brain axis seems to play a central role in the development and progression of PD. Patients with PD who report constipation display lower levels of Prevotella and have higher incidence rates of pre- and nonmotor symptoms of PD.18 Previously, researchers discovered significant links among FGIDs, PD, and psychiatric symptoms, including psychosexual dysfunction, anxiety, and depression.19 In light of recent findings detailing the possible origin of PD in the gut, psychiatrists may want to rethink the causal order once associated with these symptoms. Rather than viewing them as merely an outcome of patients suffering from PD exacerbated by FGIDs, psychiatrists should consider patients reports of psychosexual dysfunction, anxiety, and depression, along with gastric dysmotility and constipation, as early warning signs of PD.16-19

Gastroenterologists treating patients for chronic versions of FGIDs should consider referring them to neurology and neuropsychiatry for follow-up,20 and physicians should be especially attentive to patients with a history of ulcerative colitis, IBD, and Crohn disease who are older than 57 years, when risk factors for developing PD increase.21 Similarly, clinicians can gain insights into the prognosis for patients with PD by querying patients about their history of FGIDs, particularly IBD, as the onset of IBD symptoms may provide a marker for the earliest development of patients PD.1

References

1. Villumsen M, Aznar S, Pakkenberg B, Jess T, Brudek T. Inflammatory bowel disease increases the risk of Parkinsons disease: a Danish nationwide cohort study 1977-2014. Gut. 2019;68:18-24.

2. Devos D, Lebouvier T, Lardeux B, et al. Colonic inflammation in Parkinsons disease. Neurobiol Dis. 2013;50:42-48.

3. Braak H, de Vos RA, Bohl J, Del Tredici K. Gastric -synuclein immunoreactive inclusions in Meissners and Auerbachs plexuses in cases staged for Parkinsons disease-related brain pathology. Neurosci Lett. 2006;396:67-72.

4. Holmqvist S, Chutna O, Bousset L, et al. Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol. 2014;128:805-820.

5. Stokholm MG, Danielsen EH, Hamilton-Dutoit SJ, Borghammer P. Pathological -synuclein in gastrointestinal tissues from prodromal Parkinson disease patients. Ann Neurol.

2016;79:940-949.

6. Dutta SK, Verma S, Jain V, et al. Parkinsons disease: the emerging role of gut dysbiosis, antibiotics, probiotics, and fecal microbiota transplantation. J Neurogastroenterol Motil. 2019;25:363-376.

7. Jin M, Li J, Liu F, et al. Analysis of the gut microflora in patients with Parkinsons disease. Front Neurosci. 2019;13:1184.

8. Ghaisas S, Maher J and Kanthasamy A. Gut microbiome in health and disease: Linking the microbiomegutbrain axis and environmental factors in the pathogenesis of systemic and neurodegenerative diseases. Pharmacol. Ther. 2016;158:52-62.

9. Larsen JM. The immune response to Prevotella bacteria in chronic inflammatory disease. Immunology. 2019;151(4):363-374.

10. Bedarf JR, Hildebrand F, Coelho LP, et al. Functional implications of microbial and viral gut metagenome changes in early stage L-DOPA-nave Parkinsons disease patients. Genome Med. 2017;9:39.

11. Dodiya HB, Forsyth CB, Voigt RM, et al. Stress-induced disruption of intestinal barrier and dysbiosis accelerated neuroinflammation and neurodegeneration in a mouse model of Parkinsons disease: evidence for gut-brain axis dysfunction in PD. Gastroenterol. 2019;156:S-197.

12. Pan-Montojo F, Schwarz M, Winkler C, et al. Environmental toxins trigger PD-like progression via increased alpha-synuclein release from enteric neurons in mice. Sci Rep. 2012;2:898.

13. World Health Organization. The WHO Recommended Classification of Pesticides by Hazard. Geneva: World Health Organization; 2007.

14. Tanner CM, Kamel F, Ross G, et al. Rotenone, paraquat and Parkinsons disease. Environ Health Perspect. 2011;119(6):866-872.

15. Santos SF, de Oliveira HL, Yamada ES, Neves BC, Pereira Jr A. The gut and Parkinsons diseasea bidirectional pathway. Front Neurol. 2019;10:574.

16. Goetze O, Nikodem AB, Wiezcorek J, et al. Predictors of gastric emptying in Parkinsons disease. Neurogastroenterol Motil. 2006;18(5):369-375.

17. Heetun ZS and Quigley EM. Gastroparesis and Parkinsons disease: a systematic review. Parkinsonism Relat Disord. 2012;18(5):433-440.

18. Mertsalmi TH, Aho VTE, Pereira PAB, et al. More than constipationbowel symptoms in Parkinsons disease and their connection to gut microbiota. Eur J Neurol. 2017;24(11):1375-1383.

19. Makaroff L, Gunn A, Gervasoni C, Richy F. Gastrointestinal disorders in Parkinsons disease: prevalence and health outcomes in a US claims database. J Parkinsons Dis. 2011;1(1):65-74.

20. Parashar A and Udayabanu M. Gut microbiota: implications in Parkinsons disease. Parkinsonism Relat Disord. 2017;38:1-7.

21. Jankovic J and Kapadia AS. Functional decline in Parkinson disease. Arch Neurol. 2001;58:1611-1615.

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Gut Inflammation Linked to the Development of Parkinson Disease - Psychiatry Advisor