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In Gut, Villumsen et al 1 report a statistically significant association between UC and the risk of parkinsonism in a Danish nested case–control study. Patients with Crohn’s disease and UC with at least one inpatient or outpatient encounter for IBD between 1977 and 2014 were compared with age-matched and sex-matched controls (76 477 IBD; 7 548 259 controls). Follow-up started at the time of the first IBD encounter (or the corresponding date for the controls) until the first diagnosis of Parkinson’s disease or multiple system atrophy. Parkinsonism was increased among patients with UC (HR 1.35 (95% CI 1.20 to 1.52)), but not Crohn’s disease (HR 1.12 (95% CI 0.89 to 1.40)). Parkinson’s disease and multiple system atrophy were rare both in patients with IBD (0.4% and 0.02%) and non-IBD patients (0.5% and 0.01%).
These findings are consistent with basic research implicating the link between the central and enteric nervous system, also known as the gut–brain axis, in parkinsonism.2 Intestinal inflammation, a characteristic of uncontrolled IBD, may lead to a neural inflammation via the gut–brain biochemical signalling. The expression of the protein α-synuclein in both the central nervous system and intestines of patients with Parkinson’s disease and multiple system atrophy is considered the possible link. Lewy bodies are neuronal α-synuclein inclusions that are the hallmark of Parkinson’s disease, and multiple system atrophy is characterised by α-synuclein inclusions in the oligodendroglia.3 The expression of α-synuclein-associated intestinal inflammation was linked with norovirus infections in children.4 The expression of α-synuclein was thought to be the cause of the inflammation, not the effect. LRRK2 (leucine-rich repeat kinase 2), which has been linked to autophagy, is thought to play a role in protecting against opportunistic infections in early life, but later increasing the risk of Parkinson’s disease.5 LRRK2 is associated with genetic and idiopathic parkinsonism.
IBD, particularly Crohn’s disease, is also associated with LRRK2 and norovirus infection. Does Villumsen et al’s study provide support for a common cause of both IBD and parkinsonism via the gut–brain axis? From an epidemiological perspective, there is inconsistency. A study with a similar design conducted in Taiwan identified an increased risk of Parkinson’s disease in patients with Crohn’s disease (HR 1.4 (1.11–1.77)) but not UC (HR 0.94 (0.49–1.84)).6 A US study of individuals under the age of 65 found Parkinson’s disease was more common in Crohn’s disease and UC than the non-IBD population (Crohn’s disease 1.26 (1.03–1.53); UC 1.31 (1.14–1.51)).7 A chart review of records of patients with Parkinson’s found a rate of Crohn’s similar to the background rate.8 Villumsen et al found a statistically significant association for UC, but not Crohn’s disease. Neither of the population-based studies directly measured a proposed common cause. Two areas for future study include (1) comparing the rates of infection in the Crohn’s, Parkinson’s disease, jointly affected (Crohn’s and Parkinson’s) and control populations to examine a shared infectious cause, and (2) examining the LRRK2 mutations as effect modifiers of the infection–IBD–parkinsonism relationship.
How should patients with IBD, parkinsonism or their family members change their healthcare based on these findings? If α-synuclein plays a common causal role in both IBD and parkinsonism, active and passive vaccination approaches9 10 or small molecules such as anle 138b,11 a novel oligomer modulator developed based on systematic high-throughput screening, could play a role in treating or altering the risk of both conditions. Until then, the axis uniting the gut, brain, IBD and parkinsonism has not yet reached its tipping point.
Contributors SH wrote the first draft, and SH and GKW edited.
Competing interests None declared.
Patient consent Not required.
Provenance and peer review Commissioned; internally peer reviewed.
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