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ObjectiveBraak’s hypothesis states that Parkinson’s disease (PD) originates in the gastrointestinal (GI) tract, and similar associations have been established for Alzheimer’s disease (AD) and cerebrovascular diseases (CVD). We aimed to determine the incidence of GI syndromes and interventions preceding PD compared with negative controls (NCs), AD and CVD.DesignWe performed a combined case-control and cohort study using TriNetX, a US based nationwide medical record network. Firstly, we compared subjects with new onset idiopathic PD with matched NCs and patients with contemporary diagnoses of AD and CVD, to investigate preceding GI syndromes, appendectomy and vagotomy. Secondly, we compared cohorts with these exposures to matched NCs for the development of PD, AD and CVD within 5 years.ResultsWe identified 24 624 PD patients in the case-control analysis and matched 18 cohorts with each exposure to their NCs. Gastroparesis, dysphagia, irritable bowel syndrome (IBS) without diarrhoea and constipation showed specific associations with PD (vs NCs, AD and CVD) in both the case-control (odds ratios (ORs) vs NCs 4.64, 3.58, 3.53 and 3.32, respectively, all p<0.0001) and cohort analyses (relative risks (RRs) vs NCs 2.43, 2.27, 1.17 and 2.38, respectively, all p<0.05). While functional dyspepsia, IBS with diarrhoea, diarrhoea and faecal incontinence were not PD specific, IBS with constipation and intestinal pseudo-obstruction showed PD specificity in the case-control (OR 4.11) and cohort analysis (RR 1.84), respectively. Appendectomy decreased the risk of PD in the cohort analysis (RR 0.48). Neither inflammatory bowel disease nor vagotomy were associated with PD.ConclusionDysphagia, gastroparesis, IBS without diarrhoea and constipation might specifically predict Parkinson’s disease.

ObjectiveThe enteric nervous system (ENS) undergoes neuronal loss and degenerative changes with age. The cause of this neurodegeneration is poorly understood. Muscularis macrophages residing in close proximity to enteric ganglia maintain neuromuscular function via direct crosstalk with enteric neurons and have been implicated in the pathogenesis of GI motility disorders like gastroparesis and postoperative ileus. The aim of this study was to assess whether ageing causes alterations in macrophage phenotype that contributes to age-related degeneration of the ENS.DesignLongitudinal muscle and myenteric plexus from small intestine of young, mid-aged and old mice were dissected and prepared for whole mount immunostaining, flow cytometry, Luminex immunoassays, western blot analysis, enteric neural stem cell (ENSC) isolation or conditioned media. Bone marrow derived macrophages were prepared and polarised to classic (M1) or alternative (M2) activation states. Markers for macrophage phenotype were measured using quantitative RT-PCR.ResultsAgeing causes a shift in macrophage polarisation from anti-inflammatory ‘M2’ to proinflammatory ‘M1’ that is associated with a rise in cytokines and immune cells in the ENS. This phenotypic shift is associated with a neural response to inflammatory signals, increase in apoptosis and loss of enteric neurons and ENSCs, and delayed intestinal transit. An age-dependent decrease in expression of the transcription factor FoxO3, a known longevity gene, contributes to the loss of anti-inflammatory behaviour in macrophages of old mice, and FoxO3-deficient mice demonstrate signs of premature ageing of the ENS.ConclusionsA shift by macrophages towards a proinflammatory phenotype with ageing causes inflammation-mediated degeneration of the ENS.

ABSTRACTIntroduction: Gastroparesis is defined by nausea, vomiting, pain, early satiety and bloating, and characterized by delayed gastric emptying without obvious structural abnormalities. Metoclopramide is widely used, increasing gastric emptying and inhibiting nausea and vomiting. Other drugs are available in certain countries and some are used ‘off-label’ because they increase gastric emptying or inhibit emesis. However, correlation between gastroparesis symptoms and rates of gastric emptying is poor. For anti-emetic drugs, dose-ranging and Phase III trials in gastroparesis are lacking.Areas covered: Gastric motility may still be disordered, leading to nausea, even though gastric emptying is unchanged. One hypothesis is that interstitial cells of Cajal (ICC) are damaged by diabetes leading to gastric dysrhythmia and nausea. Novel approaches to treatment of nausea also include the use of ghrelin receptor agonists, highlighting a link between appetite and nausea.Expert opinion: There is an urgent need to diversify away from historical drug targets. In particular, there is a need to control nausea by regulating ICC functions and/or by facilitating appetite via ghrelin receptor agonists. It is also important to note that different upper gastrointestinal disorders (gastroparesis, chronic unexplained nausea and vomiting, functional dyspepsia) are difficult to distinguish apart, suggesting wider therapeutic opportunity.

Understanding of gastroparesis is evolving, in part because of systematic studies on the pathology, pathophysiology, and outcomes. It is clear that simply accelerating gastric emptying may not effectively control symptoms in this syndrome and more creative approaches are required that address aberrant sensation (vagal and spinal) as well as regional disturbances in motility. Further, with the growing recognition of a possible inflammatory basis, the prospects of disease modifying now seem realistic.

Gastroparesis is a chronic symptomatic disorder of the stomach characterized by delayed emptying without evidence of mechanical obstruction. Symptoms of gastroparesis include nausea, vomiting, early satiety, postprandial fullness, and upper abdominal pain. The 3 main causes are diabetic, postsurgical, and idiopathic. Diagnosis is confirmed by demonstrating delayed gastric emptying. Gastric emptying rates measured by gastric motor testing generally correlate poorly with symptoms and quality of life in patients with gastroparesis. It may be appropriate to reconsider the definition of gastroparesis, recognizing it as a broader spectrum of gastric neuromuscular dysfunction.

Given the significant impact that gut microbes have on our health, it is essential to identify key host and environmental factors that shape this diverse community. While many studies have highlighted the impact of diet on gut microbiota, little is known about how the host regulates this critical diet-microbiota interaction. In our present study, we discovered that gut IgA targeted a protein complex involved in the utilization of an important dietary polysaccharide: fructan. While the presence of dietary fructans was previously thought to allow unrestricted growth of fructan-utilizing bacteria, our work shows that gut IgA, by targeting proteins responsible for fructan utilization, provides the host with tools that can restrict the microbial utilization of such polysaccharides, thereby controlling their growth.