The gut-brain axis and Parkinson disease: clinical and pathogenetic relevance

Figures & data

Figure 1. Summary of pathophysiological mechanisms associated with the gastrointestinal disturbances in patients with PD. The pathophysiology of these symptoms is complex and involves both central and peripheral mechanisms. LBs: Lewy bodies; BG: basal ganglia; DMV: dorsal motor nucleus of the vagus; GI: gastrointestinal; VN: vagus nerve; SIBO: small intestinal bacterial overgrowth; PPIs: proton-pump inhibitors; ENS: enteric nervous system.

Table 1. Clinical, diagnostic and therapeutic features of the main GI disturbances in PD.

GI disturbance	Prevalence	Diagnosis	Non-pharmacological management	Pharmacological treatment	Surgical treatment
Sialorrhea (or drooling of saliva)	10–81%		Chew gum, rehabilitation of deglutition	Oral glycopyrrolate, sublingual atropine drops, botulinum toxin injections into salivary glands
Oropharyngeal dysphagia	35–80%	FEES, barium swallow studies, videofluoroscopy, HRM	Postural changes, reduced meal volumes, eating slowing, use of liquid thickeners, EMST, VAST	Levodopa (?)	DBS (?)
Esophageal dysphagia	∼ 30%	HRM with or without fluoroscopy	Same as oropharyngeal dysphagia	Botulinum toxin injections in the distal esophageus; Levodopa (?)	STN DBS (?); pneumatic dilation or surgical therapies for EGJ outflow obstruction
Delayed gastric emptying (gastroparesis)	70–100% (symptoms are reported only in 25–45% of cases)	Gastric emptying scintigraphy; wireless motility capsule	Eating small, frequent meals with low fibre and low-fat content	Domperidone; highly selective 5-HT4 agonists (prucalopride, mosapride – not approved in the United States); botulinum toxin injections into the pyloric sphincter; ghrelin agonist (?)	Gastric pacemaker implantation (?)
SIBO	25–54%	Lactulose or glucose breath tests	Probiotics	Antibiotics; correction of SIBO causes (e.g., prokinetic drugs)
Constipation	∼ 50% (range, 8–70%)	Colonic transit using radio opaque markers, MRI defecography, HRAM	Increasing high fibre dietary and fluid intake, performing physical activity, removing aggravating medications, probiotics and prebiotic fibre. For defecatory dyssynergia: biofeedback therapy	Oral bulking agents, osmotic laxatives (macrogol), lubiprostone. For defecatory dyssynergia: levodopa, apomorphine, botulinum toxin injections into the external anal sphincter and puborectalis

EGJ: esophagogastric junction; EMST: expiratory muscle strength training; FEES: flexible endoscopic evaluation of swallowing; HRAM: high-resolution anorectal manometry; HRM: high-resolution manometry; SIBO: small intestinal bacterial overgrowth; STN DBS: subthalamic nucleus deep brain stimulation; VAST: video-assisted swallowing therapy; (?): contrasting or insufficient results that require further confirmation.

Figure 2. A proposed schematic representation of the pathways implicated in the gut-brain axis in PD. (1) An alteration in the composition of the gut microbiome towards a more pro-inflammatory profile has been shown in patients with PD. (2) The increased gut permeability seen in patients with PD could expose enteric neurons to bacterial derived pro-inflammatory products; the activation of enteric glial cells (EGC) within the gastrointestinal tract of PD patients, seen in the early phases of the disease, might contribute to amplify the impairment of the intestinal barrier and facilitate the spread of pathological α-synuclein within the ENS. Alternatively, bacterial products could be sensed by the EECs dispersed within the gut epithelium; these cells might be a site of initial α-synuclein aggregation which can then be transferred to the VN. (3) Either through the mediation of the ENS or by direct synapsing, pathological α-synuclein can reach the vagal nerve and, due to its cell-to-cell transmission properties, retrogradely propagate to the brain. (4) Within the brain, pathological α-synuclein spreads within different areas resulting in loss of nigrostriatal dopaminergic neurons and development of motor symptoms of PD. ENS: enteric nervous system; EGC: enteric glial cell; EEC: enteroendocrine cell; LPS: lipopolysaccharide; SCFA: short-chain fatty acids.

Data availability statement

Data sharing is not applicable to this article as no new data were created or analysed in this study.