Fig. 2.

The gut-brain axis in Parkinson’s disease (PD). In this concept of PD pathogenesis, macrophages in the gut lamina propria are induced by secreted pro-inflammatory cytokines in individuals carrying gain-of-function LRRK2 variants that express increased levels of activated LRRK2; stimulation of cells by α-synuclein from enteric nerves may also occur at this site but this is still unproven. Macrophages thus stimulated that gain entry into the circulation are attracted into brain tissue by chemokine-secreting microglia and in the brain tissue are induced to produce pathogenic inflammatory cytokines by as yet undefined stimuli, possibly including α-synuclein once again; these cytokines cause or aggravate neural degeneration. Also depicted are small intestinal Paneth cells whose function is regulated in part by LRRK2; thus, LRRK2 variants that affect this function and adversely regulate the composition of the gut microbiome may lead to PD by promoting gut inflammation.