Reply to: Mild Chronic Colitis Triggers Parkinsonism in LRRK2 Mutant Mice through Activating TNF‐α Pathway

Gut microenvironmental changes as a potential trigger in Parkinson’s disease through the gut–brain axis

“…It is though that TLR4, a pattern recognition receptor, plays a crucial role in mediating the disease process because an elevation of TLR4 in colonic tissues and TLR4-downstream inflammatory mediators [e.g., nuclear factor-κB (NF-κB) and TNF-α] has been observed in PD patients and mouse models of PD. Knockout of TLR4 or treatment with TNF-α antagonist or TLR4 blockers mitigates neuroinflammation, dopaminergic neuronal loss, and motor dysfunction in both cellular and rodent models of PD [ 66 , 76 , 78 , 79 ]. As previously mentioned, intestinal inflammation could trigger the expression of enteric alpha-synuclein and vice versa [ 62 , 80 ], with intestinal inflammation per se increasing the permeability of the blood–brain barrier (BBB), promoting microgliosis, and aggravating neuronal loss through upregulation of systemic pro-inflammatory cytokines and neuroinflammation [ 74 ].…”

“…2 ). The complex interplay between genetic risk factors in the host and environmental factors, especially gut microorganisms or gut metabolites, has been examined in multiple rodent models of PD (Table 2 ) [ 76 , 77 , 113 , 122 , 169 – 173 ]. In addition, genome-wide association studies have identified numerous genetic risks that increase susceptibility to sporadic PD, and several genes are related to gut microbial regulation and intestinal inflammation, including pattern recognition receptors TLR1 and TLR2, peptidoglycan recognition protein, and MUC2, a component of the mucosal layer that protects the intestinal epithelial barrier [ 174 ].…”

“…LRRK2 is also highly expressed in peripheral immune cells and up-regulated during inflammation in response to pro-inflammatory cytokines and activated TLRs [ 184 , 185 ]. Elevated LRRK2 kinase activity promotes inflammatory responses, including activation of the inflammasome and NF-κB pathway, leading to increased secretion of pro-inflammatory cytokines (e.g., TNF-α and IL-1ß), which assist in pathogen clearance but also worsen colitis, chronic neuroinflammation, and dopaminergic neuronal loss in rodent models [ 171 , 182 , 186 , 187 ]. Furthermore, treatment with anti-TNF-α monoclonal antibody greatly reduces gut inflammation and neuroinflammation, mitigates dopaminergic neuronal loss, and alleviates motor symptoms exacerbated by chronic colitis in a transgenic LRRK2 p.G2019S mouse model [ 187 ].…”

The Pathological Mechanism Between the Intestine and Brain in the Early Stage of Parkinson's Disease

“…Through the analysis of colon biopsies from patients with PD, it has been determined that proinflammatory cytokines (TNF-α, IF-γ, IL-6, and IL-1β) and glial cell markers GFAP and SOX-10 are significantly increased in patients with PD (Devos et al, 2013). Recent findings demonstrated that chronic colitis promotes parkinsonism in genetically susceptible mice, and TNF-α plays a detrimental role in the gut-brain axis of PD (Lin et al, 2021).…”

The Role of Insular Cortex in Gut‐Inflammation Memory: What Does It Mean for Parkinson's Disease?

“…For example, a recent study showed that LRRK2 G2019S mice were more vulnerable to DSS‐induced colitis than controls with higher α‐synuclein colonic expression, more severe locomotor defect, and dopaminergic neuron loss 4 . The authors also showed that patients with PD had mild gut inflammation and increased TNF‐α levels 4 .…”