Three-Dimensional Imaging of the Enteric Nervous System in Human Pediatric Colon Reveals New Features of Hirschsprung's Disease.

BACKGROUND & AIMS: Hirschsprung's disease is defined by the absence of the enteric nervous system (ENS) from the distal bowel. Primary treatment is "pull-through" surgery to remove bowel that lacks ENS, with reanastomosis of "normal" bowel near the anal verge. Problems after pull-through are common, and some may be due to retained hypoganglionic bowel (ie, low ENS density). Testing this hypothesis has been difficult because counting enteric neurons in tissue sections is unreliable, even for experts. Tissue clearing and 3-dimensional imaging provide better data about ENS structure than sectioning. METHODS: Regions from 11 human colons and 1 ileal specimen resected during Hirschsprung's disease pull-through surgery were cleared, stained with antibodies to visualize the ENS, and imaged by confocal microscopy. Control distal colon from people with no known bowel problems were similarly cleared, stained, and imaged. RESULTS: Quantitative analyses of human colon, ranging from 3 days to 60 years old, suggest age-dependent changes in the myenteric plexus area, ENS ganglion area, percentage of myenteric plexus occupied by ganglia, neurons/mm2, and neuron Feret's diameter. Neuron counting using 3-dimensional images was highly reproducible. High ENS density in neonatal colon allowed reliable neuron counts using 500-µm2 × 500-µm2 regions (36-fold smaller than in adults). Hirschsprung's samples varied 8-fold in proximal margin enteric neuron density and had diverse ENS architecture in resected bowel. CONCLUSIONS: Tissue clearing and 3-dimensional imaging provide more reliable information about ENS structure than tissue sections. ENS structure changes during childhood. Three-dimensional ENS anatomy may provide new insight into human bowel motility disorders, including Hirschsprung's disease.

The enteric nervous system relays psychological stress to intestinal inflammation.

Mental health profoundly impacts inflammatory responses in the body. This is particularly apparent in inflammatory bowel disease (IBD), in which psychological stress is associated with exacerbated disease flares. Here, we discover a critical role for the enteric nervous system (ENS) in mediating the aggravating effect of chronic stress on intestinal inflammation. We find that chronically elevated levels of glucocorticoids drive the generation of an inflammatory subset of enteric glia that promotes monocyte- and TNF-mediated inflammation via CSF1. Additionally, glucocorticoids cause transcriptional immaturity in enteric neurons, acetylcholine deficiency, and dysmotility via TGF-ß2. We verify the connection between the psychological state, intestinal inflammation, and dysmotility in three cohorts of IBD patients. Together, these findings offer a mechanistic explanation for the impact of the brain on peripheral inflammation, define the ENS as a relay between psychological stress and gut inflammation, and suggest that stress management could serve as a valuable component of IBD care.

Delayed Gastric Emptying After Pancreaticoduodenectomy: an Analysis of Risk Factors and Cost.

INTRODUCTION: Delayed gastric emptying (DGE) is a common complication after pancreaticoduodenectomy (PD), yet it remains incompletely understood. The International Study Group of Pancreatic Surgery (ISGPS) in 2007 defined a three-tiered grading system to standardize studies of DGE. METHODS: In this study, 721 patients undergoing PD between 2006 and 2012 were retrospectively categorized by the ISGPS DGE criteria, as well as a modified grading system (termed primary DGE) if, on retrospective review, DGE was not believed to be a sequela of a separate complication. Predictive factors and associated outcomes were determined. RESULTS: ISGPS-defined DGE occurred in 140 (19.4%) patients. In a multivariate analysis, predictors of ISGPS-defined DGE included abdominal infection (odds ratio (OR) 5.5, p < 0.001), male gender (OR 1.92, p = 0.007), smoking history (OR 1.75 p = 0.033), and periampullary adenocarcinoma (OR 1.66, p = 0.041). Primary DGE occurred in 12.2% of patients. Predictors included abdominal infection (OR 3.15, p < 0.001) and smoking history (OR 2.04, p = 0.008). Median hospital charges increased over $10,000 with each severity grade of DGE (p < 0.001). CONCLUSION: DGE is common after PD and contributes substantially to cost. DGE is frequently a secondary complication of abdominal infection, and interventions that limit such complications may be the most effective strategy toward preventing DGE.