Gut Macrophages Drive Parkinson's Spread from Intestine to Brain

Parkinson's disease (PD) is increasingly understood to begin not in the brain but in the gut. Constipation and enteric nervous system (ENS) dysfunction precede motor symptoms by decades, and post-mortem evidence shows early Lewy body pathology in the intestine spreading caudo-rostrally to the brainstem. Yet the cellular mechanisms initiating this gut-to-brain cascade remained poorly defined — until now.

This landmark Nature study by De Schepper, Konstantellos, Conway, Sokolova and colleagues identifies muscularis externa macrophages (ME-Macs) as early cellular initiators of α-synuclein (αS) pathology. ME-Macs are long-lived, self-renewing tissue-resident immune cells embedded in the myenteric plexus that normally sustain ENS integrity by producing neurotrophic factors and clearing cellular debris. In ageing mice, ME-Macs already accumulate αS and express PD-risk genes Gba1 and Lrrk2, making them prime candidates for disease initiation.

Using two complementary mouse models — 3KL αS transgenic mice (Thy1-driven E46K-amplified αS) and direct muscularis injection of patient-derived αS preformed fibrils — the authors showed that ME-Macs, rather than enteric neurons, are the primary cells containing misfolded, phosphorylated (s129p+) αS in the ENS. This αS accumulation coincided with a transcriptional signature of endolysosomal dysfunction in ME-Macs, suggesting impaired proteostasis rather than simple passive uptake. The authors also demonstrated that ME-Macs orchestrate local T cell expansion within the ENS. As αS pathology progressed, T cells migrated from the gut to the CNS via the dura mater — a meningeal immune gateway — amplifying neuroinflammation in the brain.

The functional significance of ME-Macs was demonstrated through targeted depletion: injecting anti-CSF1R and anti-CCR2 antibodies locally into the muscularis dramatically reduced αS pathology in both the ENS and CNS, abolished T cell trafficking along the gut–brain axis, and improved motor performance and dopaminergic neuron survival. Importantly, enteric neuron populations were preserved after ME-Mac depletion, confirming that ME-Macs — not neurons — are the drivers of spreading pathology.

The study also examined human tissue, finding αS-laden macrophages in the muscularis of PD patient gut biopsies, lending direct translational relevance. Collectively, these findings reframe ME-Macs as critical early-stage modulators of PD pathogenesis and suggest that gut immune surveillance could be leveraged for biomarker discovery or therapeutic intervention well before motor symptoms emerge.