Colonic inflammation in Parkinson's disease
Highlights
► Pro-inflammatory cytokines expression is up regulated in the colon of PD patients. ► Glial markers expression is up regulated in the colon of PD patients. ► Gastrointestinal inflammation is likely to be involved in PD pathophysiology.
Introduction
An accumulating body of evidence has emerged in the last 15 years to suggest that inflammation-derived oxidative stress and cytokine-dependent toxicity may contribute to substantia nigra degeneration and accelerate disease progression in Parkinson's disease (PD) (Hirsch et al., 2012). The involvement of inflammation in PD pathogenesis is supported by the occurrence of infiltration of activated microglia and T lymphocytes in post-mortem PD brains (Brochard et al., 2009, McGeer et al., 1988) and by the accumulation of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma), interleukin-6 (IL-6) and interleukin-1 beta (IL-1 beta) in the brain and cerebrospinal fluid of PD patients (Blum-Degen et al., 1995, Mogi et al., 1994a, Mogi et al., 1994b, Mogi et al., 1996, Reale et al., 2009). As many of the cytokines up regulated in PD are expressed at high levels in glial cells (Farina et al., 2007), it is likely that glial dysregulation is critically involved in PD neuroinflammation (Damier et al., 1993).
Lewy pathology in PD extends well beyond the central nervous system (CNS) and also affects peripheral autonomic neuronal circuits, among which is the enteric nervous system (ENS) (Beach et al., 2009, Wakabayashi et al., 1988). The ENS is an integrative neuronal network organized in two major ganglionated plexuses, the myenteric plexus mainly involved in the control of smooth muscle activity and the submucosal plexus, which regulates secretion and microvasculature (Benarroch, 2007, Schemann and Neunlist, 2004). It is sometimes referred to as “the-brain-in-the-gut” because of its similarities with the CNS (Benarroch, 2007, Schemann and Neunlist, 2004). Indeed, the ENS contains a variety of functionally distinct enteric neurons and harbors a prominent component of glial cells (enteric glial cells, EGC), which, likewise astrocytes of the CNS, contribute to support, protect and maintain the neural networks (Bassotti et al., 2007, Savidge et al., 2007). In PD, Lewy pathology is distributed from the esophagus to the rectum and affects both the myenteric and submucosal plexuses (Beach et al., 2009, Lebouvier et al., 2010b, Pouclet et al., 2012b, Wakabayashi et al., 1988). Others and we have recently shown that routine colonic biopsies enable a comprehensive assessment of the submucosal plexus and the detection of Lewy pathology in PD (Lebouvier et al., 2008, Lebouvier et al., 2010a, Lebouvier et al., 2010b, Pouclet et al., 2012a, Pouclet et al., 2012b, Shannon et al., 2012).
Structural and functional abnormalities of the ENS and especially of the EGC are observed in inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis (Neunlist et al., 2003, von Boyen et al., 2011) and ablation of enteric glia in mice is associated with the development of severe gut inflammation (Aube et al., 2006, Bush et al., 1998, Cornet et al., 2001). Three single nucleotide polymorphisms in the CARD15 gene known to be associated with Crohn's disease have been shown to be over-represented in PD patients, suggesting that, beyond brain, inflammation may occur in the gastrointestinal tract in PD (Bialecka et al., 2007). We therefore undertook the present study to investigate whether changes in the expression of the main pro-inflammatory cytokines and glial markers do occur in colonic biopsies from PD patients and to determine whether these changes are correlated with clinical features and dopaminergic treatment.
Section snippets
Subjects
A total of 33 subjects participated in this study, 19 PD patients and 14 age-matched healthy controls. Clinical diagnosis of PD was made according to the United Kingdom PD Society Brain Bank clinical diagnostic criteria (Hughes et al., 1992). Control subjects were healthy patients who required a total colonoscopy for colorectal cancer screening. All controls subjects underwent a detailed neurological examination to rule out PD symptoms and cognitive deficiency. PD patients with a positive
Results
Clinical features of the study population are shown in Table 1. Age and sex did not differ significantly between patients and controls.
Discussion
As far as we know, our study is the first to show that PD is associated with gut inflammation. The pro-inflammatory cytokine profile observed in our PD patients, namely an increase in the expression of TNF-alpha, IFN-gamma, IL-6 and IL-1 beta is strikingly similar to the one observed in IBD (Matsuda et al., 2009, Reimund et al., 1996). We also provide evidence that enteric inflammation in PD is tightly associated with glial dysregulation as the expression levels of GFAP and Sox-10 in colonic
Acknowledgments
This work was supported by a grant from the Michael J. Fox Foundation for Parkinson's Research, from France Parkinson and from Nantes University Hospital (Direction de la Recherche Clinique). Work in Michel Neunlist's lab is supported by CECAP (Comité d'Entente et de Coordination des Associations de Parkinsoniens), ADPLA (Association des Parkinsoniens de Loire Atlantique), FFPG (Fédération française des groupements parkinsoniens) and Parkinsoniens de Vendée.
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DD and TL contributed equally to this work.