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Background Leucine‐rich repeat kinase 2 (LRRK2) is a common risk gene for Parkinson's disease (PD) and inflammatory bowel disorders. However, the penetrance of the most prevalent LRRK2 mutation, G2019S, is <50%. Factors other than genetic mutations are needed in PD process. Objectives To examine whether and how gut inflammation may act as an environmental trigger to neurodegeneration in PD. Methods A mild and chronic dextran sodium sulfate (DSS)‐induced colitis mice model harboring LRRK2 G2019S mutation was established. The colitis severity, immune responses, locomotor function, dopaminergic neuron, and microglia integrity were compared between littermate controls, transgenic LRRK2 wild type (WT), and LRRK2 G2019S mice. Results The LRRK2 G2019S mice are more vulnerable to DSS‐induced colitis than littermate controls or LRRK2 WT animals with increased intestinal expressions of pattern‐recognition receptors, including toll‐like receptors (TLRs), nuclear factor (NF)‐κB activation, and pro‐inflammatory cytokines secretion, especially tumor necrosis factor (TNF)‐α. Notably, the colonic expression of α‐synuclein was significantly increased in LRRK2 G2019S colitis mice. We subsequently observed more aggravated locomotor defect, microglia activation, and dopaminergic neuron loss in LRRK2 G2019S colitis mice than control animals. Treatment with anti‐TNF‐α monoclonal antibody, adalimumab, abrogated both gut and neuroinflammation, mitigated neurodegeneration, and improved locomotor function in LRRK2 G2019S colitis mice. Finally, we validated increased colonic expressions of LRRK2, TLRs, and NF‐κB pathway proteins and elevated plasma TNF‐α level in PD patients compared to controls, especially in those with LRRK2 risk variants. Conclusions Our findings demonstrate that chronic colitis promotes parkinsonism in genetically susceptible mice and TNF‐α plays a detrimental role in the gut‐brain axis of PD. © 2021 International Parkinson and Movement Disorder Society

BackgroundMutations in leucine-rich repeat kinase 2 (LRRK2) comprise a common genetic risk factor for Parkinson’s disease (PD) and inflammatory bowel disease (IBD). We investigated the expression of LRRK2 in colonic biopsies obtained from a cohort of PD patients and healthy controls.MethodsA cohort of 51 PD patients and 40 age- and gender-matched controls who have colonic biopsied samples were recruited. Among these participants, 26 individuals (12 PD patients and 14 controls) had a series of colon biopsies. For the patients with PD, the first biopsies were taken before the PD diagnosis. The colonic expression of LRRK2 was assayed by immunohistochemical staining.ResultsThe fraction of LRRK2-positive cells among the total cell count in biopsied colonic tissues was significantly higher in PD patients than controls (0.81% ± 0.53% vs. 0.45% ± 0.39%; P = 0.02). Colonic LRRK2 immunoreactivity was higher in those with LRRK2 genetic variants compared to those with wild type LRRK2 (2.44% ± 1.15% vs. 0.21 ± 0.13%, P &lt; 0.01). Age had no effect on LRRK2 expression (P = 0.96). LRRK2 expression correlated with disease severity in regards to motor symptoms measured by the UPDRS part III scores (r = 6335, P &lt; 0.001) and cognitive dysfunction measured by the mini-mental status examination scores (r = -0.5774, P &lt; 0.001). PD patients in the prodromal phase had a steeper increase in colonic LRRK2 expression compared to controls during the serial colon biopsy assessment (P &lt; 0.01).ConclusionColonic LRRK2 expression was increased in PD patients compared to controls, and the expression level correlated with disease severity.

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