From the Gut to the Brain: Intestinal Inflammation as a Driver of Parkinsonian Neuropathology Madelyn C. Houser1, W. Michael Caudle2, Jianjun Chang1, Kathleen M. Shannon3, Ali Keshavarzian4, Malú G. Tansey*1 1Department of Physiology, Emory University School of Medicine; 2Department of Environmental Health, Emory University Rollins School of Public Health; 3Department of Neurology, University of Wisconsin School of Medicine and Public Health; 4Department of Internal Medicine, Rush Medical College
The etiology of Parkinson's disease (PD) remains uncertain, and by the time the characteristic motor impairments manifest, extensive, irreversible neurodegeneration has already occurred. Gastrointestinal problems are also common features of PD, however, and they frequently manifest years before the development of motor symptoms. This has led to the theory that PD pathology could initiate in the intestine before advancing to the central nervous system (CNS). Given the abundant evidence supporting a role for inflammation in neurodegenerative disease, we investigated whether intestinal inflammation could be mediating the progression from digestive dysfunction to CNS neuropathology in PD.
We first determined that PD patients do exhibit indications of intestinal inflammation. In keeping with published reports of elevated levels of proinflammatory cytokines in the GI tract in PD, we found evidence of substantially increased immune cell infiltration, proinflammatory activity, and oxidative stress in colonic biopsies from PD patients compared to controls. We then utilized mouse models of colitis, which induced the same kinds of inflammatory mediators upregulated in PD colon tissue, to evaluate the impact of colonic inflammation on neuron health and function in the brain. We discovered that the induction of damage and inflammation in the intestine was sufficient to perturb the functionality of dopaminergic neurons on its own without causing overt terminal loss, and that it increased sensitivity to the neurodegenerative effects of MPTP. The severity of neurological changes correlated with the severity of colitis, further substantiating the relationship between peripheral inflammatory activity and central neuropathology. Our findings confirm that intestinal inflammation is present in PD and that such inflammation can induce dopaminergic neuropathology, lending support for the gut-to-brain theory of PD pathogenesis.
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