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Letter
GI infections are associated with an increased risk of Parkinson’s disease
  1. Michael Nerius1,
  2. Gabriele Doblhammer1,
  3. Gültekin Tamgüney2,3
  1. 1 Deutsches Zentrum für Neurodegenerative Erkrankungen, Bonn, Nordrhein-Westfalen, Germany
  2. 2 Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Nordrhein-Westfalen, Germany
  3. 3 Institute of Complex Systems, Structural Biochemistry (ICS-6), Forschungszentrum Jülich, Jülich, Nordrhein-Westfalen, Germany
  1. Correspondence to Dr Gültekin Tamgüney, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany; tamguney{at}gmail.com

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We have read with interest the recent publication of Perez-Pardo and colleagues1 reporting the role of the TLR4 in the gut–brain axis in Parkinson’s disease (PD). These findings prompted us to investigate the role of common GI infections (GIIs) in the pathogenesis of PD. In this prospective cohort study, we assessed the risk of PD in patients who previously suffered from GIIs compared with the control group not exposed to GIIs (table 1). At study entry (1 January 2005), the analysis sample from health claims data of the largest German health insurer consisted of2 28 485 individuals aged 50 years and older, which were followed for a mean time of 8.6 years (median=11.0 years; IQR=7.6 years). PD and GIIs were defined by ICD-10 codes as described in the supplementary material. Overall, 6195 individuals (2.7%) developed PD and 50 492 individuals (22.1%) were affected by any GII during the observation period between 2005 and 2015. The most frequent GIIs were those that caused infectious gastroenteritis and colitis of unspecified origin (IGCUs; 39 093 individuals, 17.1%), followed by viral intestinal infections (VIIs; 9328 individuals, 4.1%) and bacterial intestinal infections (BIIs; 9298 individuals, 4.1%). The cumulative incidence of PD was significantly higher among individuals with GIIs (p<0.001, online  supplementary figure S1). Multivariable analyses (table 2) using Cox regression to compute HRs revealed an increased risk of PD in patients with GIIs when compared with the control group (HR=1.42; 95% CI 1.33 to 1.52). Subgroup analyses (table 2) revealed positive associations of GIIs for men (HR=1.48; 95% CI 1.34 to 1.63), women (HR=1.38; 95% CI 1.27 to 1.50), individuals aged 70 years or older (HR=1.25; 95% CI 1.04 to 1.49) and individuals with (HR=1.40; 95% CI 1.23 to 1.59) or without chronic obstructive pulmonary disease (HR=1.43; 95% CI 1.33 to 1.54). To solidify our results, we performed sensitivity analyses and found no remarkable changes compared with our primary analysis (online supplementary table S1). In a secondary analysis, where we considered GIIs separately (online supplementary table S2), BIIs (HR=1.30; 95% CI 1.12 to 1.50), VIIs (HR=1.31; 95% CI 1.14 to 1.50) and IGCUs (HR=1.34; 95% CI 1.24 to 1.44) were each associated with an increased risk of PD.

Supplementary file 1

Table 1

Characteristics of the study population by exposition to GIIs, no (%)

Table 2

Incidence rates* and HRs of PD for the total sample and subgroups

Our findings suggest that GIIs are associated with an increased risk of PD. In sporadic PD, Lewy pathology defined by aggregated alpha-synuclein is first observed in the olfactory bulb and the enteric plexuses from where it propagates via the vagus nerve to the dorsal motor nucleus in the central nervous system (CNS).2 This prion-like ability of pathological alpha-synuclein to retrogradely spread from the periphery to the CNS is supported by a growing body of experimental work in rodents.3–5 In the light of these findings, our results point to the missing link of what may cause alpha-synuclein pathology in the enteric nervous system (ENS): bacterial and viral pathogens, which breach the mucosal lining of the GI tract during GIIs, may trigger aggregation of alpha-synuclein in enteric neurons and initiate its retrograde transport to the CNS. Several species of gut bacteria express amyloid proteins, which could potentially cross-seed aggregation of alpha-synuclein.6 In line with this, oral challenge of rats with a wild-type Escherichia coli strain expressing the extracellular amyloid curli led to deposition of pathological alpha-synuclein in their ENS and subsequently CNS.7 Another study in patients showed that expression of alpha-synuclein in enteric neurites of the GI tract was elevated in response to BIIs and VIIs.8 Also, biopsy samples from intestinal allograft subjects after a norovirus infection showed elevated alpha-synuclein expression in enteric neurons that persisted months after the virus was no longer detected.8 Overall, our findings are consistent with the concept that in some patients PD may start in the GI tract.

Acknowledgments

We are grateful to Jürgen-Bernhard Adler and Christian Günster of the of the Allgemeine Ortskrankenkasse Research Institute (WIdO) for providing the data. We would like to thank Renée Lüskow for English language editing.

References

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Footnotes

  • Contributors MN performed the statistical analysis and contributed to the writing of the manuscript. GD and GT conceived the study, participated in the statistical analysis and contributed to the writing of the manuscript. All authors were involved in the critical revision of the manuscript.

  • Funding The authors have received funding only through their employer the German Center for Neurodegenerative Diseases and the Heinrich-Heine-Universität Düsseldorf.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement The scientific research institute of the AOK (WIdO) has strict rules regarding data sharing because of the fact that health claims data are a sensible data source and have ethical restrictions imposed due to concerns regarding privacy. Anonymised data are available to all interested researchers on request. Interested individuals or institutions that wish to request access to the health claims data of the AOK should contact the WIdO (http://www.wido.de/, mail: wido@wido.bv.aok.de).

  • Patient consent for publication Not required.

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