AbstractBackgroundLeucine‐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.ObjectivesTo examine whether and how gut inflammation may act as an environmental trigger to neurodegeneration in PD.MethodsA 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.ResultsThe 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.ConclusionsOur 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