Lewy body diseases and the gut

Abstract

Gastrointestinal (GI) involvement in Lewy body diseases (LBDs) has been observed since the initial descriptions of patients by James Parkinson. Recent experimental and human observational studies raise the possibility that pathogenic alpha-synuclein (⍺-syn) might develop in the GI tract and subsequently spread to susceptible brain regions. The cellular and mechanistic origins of ⍺-syn propagation in disease are under intense investigation. Experimental LBD models have implicated important contributions from the intrinsic gut microbiome, the intestinal immune system, and environmental toxicants, acting as triggers and modifiers to GI pathologies. Here, we review the primary clinical observations that link GI dysfunctions to LBDs. We first provide an overview of GI anatomy and the cellular repertoire relevant for disease, with a focus on luminal-sensing cells of the intestinal epithelium including enteroendocrine cells that express ⍺-syn and make direct contact with nerves. We describe interactions within the GI tract with resident microbes and exogenous toxicants, and how these may directly contribute to ⍺-syn pathology along with related metabolic and immunological responses. Finally, critical knowledge gaps in the field are highlighted, focusing on pivotal questions that remain some 200 years after the first descriptions of GI tract dysfunction in LBDs. We predict that a better understanding of how pathophysiologies in the gut influence disease risk and progression will accelerate discoveries that will lead to a deeper overall mechanistic understanding of disease and potential therapeutic strategies targeting the gut-brain axis to delay, arrest, or prevent disease progression.

Keywords: Dementia with Lewy bodies; Gastrointestinal tract; Immunity; Inflammation; Microbiome; Parkinson’s disease; Parkinson’s disease dementia.

Fig. 1

Graphical representation of the major neural pathways connecting the GI tract and brain. The vagus nerve contains both afferent and efferent fibers and innervates the esophagus, stomach, small intestine and proximal colon. Branched endings represent axonal endings. Cell bodies of the motor branch of the vagus reside in the dorsal motor nucleus of the vagus and those of the sensory branch are in the nodose ganglia. The celiac, superior and inferior mesenteric ganglia integrate sensory and motor inputs to the upper and lower GI tract and pathways carry signals to and from the distal colon and rectum. All nerves contain ⍺-syn and are subject to templating and propagating misfolded ⍺-syn thus representing routes of transport to susceptible brain regions. The vagus nerve richly innervates the upper GI tract and provides a direct route for ⍺-syn spread to the brain. (Modified from [33] and [34])

Fig. 2

Diagram depicting the arrangement of the enteric nervous system (ENS) in the gut. In the small and large intestines, nerve cell bodies reside in ganglia of the myenteric or submucosal plexi. The myenteric plexus lies between the circular and longitudinal muscle layers of the bowel wall. Soma of the submucosal plexus are found in ganglia between the muscularis mucosa and circular muscle layer and extend neurites to crypts and villi of the bowel wall. Enteric and vagal fibers abut but do not penetrate the intestinal mucosa. In this location, any misfolded ⍺-syn (red dots) of mucosal origin (e.g., EECs, green) may spread to the nervous system. (Modified from [35])

Fig. 3

Co-culture of intestinal organoids and sensory neurons. A Cartoon depicting an experiment in which intestinal organoids from a transgenic mouse expressing human ⍺-syn (tgSNCA^A53T) are co-cultured with nodose neurons from mice devoid of ⍺-syn (Snca^−/−). Enteroendocrine cells (green) containing ⍺-syn (red) are dispersed among other cell types which are mostly enterocytes. Grown from intestinal crypt fragments or isolated stem cells, organoids form spheroids comprised of a single layer of mucosa surrounding a central lumen. B Nodose ganglion neurons (cyan) grown in gut organoid co-culture often contact EECs (green). Spread of ⍺-syn from tgSNCA^A53T EECs to nodose neurons from Snca^−/− mice has been demonstrated in culture [75]. This transer is depicted in the representative confocal images (scale bar is 3 μm)

Fig. 4

Publications supporting key concepts highlighted in this review for GI involvement in the pathogenesis and pathophysiology of Lewy body diseases