Impaired Expression of Neuregulin 1 and Nicotinic Acetylcholine Receptor β4 Subunit in Diverticular Disease

Abstract

Neuregulin 1 (NRG1) regulates the expression of the nicotinic acetylcholine receptor (nAChR) and is suggested to promote the survival and maintenance of the enteric nervous system (ENS), since deficiency of its corresponding receptor complex ErbB2/ErbB3 leads to postnatal colonic aganglionosis. As diverticular disease (DD) is associated with intestinal hypoganglionosis, the NRG1-ErbB2/ErbB3 system and the nAChR were studied in patients with DD and controls. Samples of tunica muscularis of the sigmoid colon from patients with DD (n = 8) and controls (n = 11) were assessed for mRNA expression of NRG1, ErbB2, and ErbB3 and the nAChR subunits α3, α5, α7, β2, and β4. Site-specific gene expression levels of the NRG1-ErbB2/3 system were determined in myenteric ganglia harvested by laser microdissection (LMD). Localization studies were performed by immunohistochemistry for the NRG1-ErbB2/3 system and nAChR subunit β4. Rat enteric nerve cell cultures were stimulated with NRG1 or glial-cell line derived neurotrophic factor (GDNF) for 6 days and mRNA expression of the aforementioned nAchR was measured. NRG1, ErbB3, and nAChR subunit β4 expression was significantly down-regulated in both the tunica muscularis and myenteric ganglia of patients with DD compared to controls, whereas mRNA expression of ErbB3 and nAChR subunits β2, α3, α5, and α7 remained unaltered. NRG1, ErbB3, and nAChR subunit β4 immunoreactive signals were reduced in neuronal somata and the neuropil of myenteric ganglia from patients with DD compared to control. nAChR subunit β4 exhibited also weaker immunoreactive signals in the tunica muscularis of patients with DD. NRG1 treatment but not GDNF treatment of enteric nerve cell cultures significantly enhanced mRNA expression of nAchR β4. The down-regulation of NRG1 and ErbB3 in myenteric ganglia of patients with DD supports the hypothesis that intestinal hypoganglionosis observed in DD may be attributed to a lack of neurotrophic factors. Regulation of nAChR subunit β4 by NRG1 and decreased nAChR β4 in patients with DD provide evidence that a lack of NRG1 may affect the composition of enteric neurotransmitter receptor subunits thus contributing to the intestinal motility disorders previously reported in DD.

The Endocrine Disruptor Bisphenol A (BPA) Affects the Enteric Neurons Immunoreactive to Neuregulin 1 (NRG1) in the Enteric Nervous System of the Porcine Large Intestine

“…The important roles of NRG1 in the development of the ENS are supported by the fact that in laboratory animals deprived of NRG1 or ErbB receptors, a reduction in the number of synapses and enteric ganglia has been noted [ 75 , 76 ]. Moreover, it is known that disturbances of NRG1 expression in the intestinal nervous structures occur during gastrointestinal diseases, including diventricular disease and Hirschsprung’s disease [ 18 , 22 , 35 ]. Previous studies also strongly suggest the roles of NRG1 localized in the neuronal cells of the myenteric plexus in regulatory processes connected with gastrointestinal motility [ 3 ].…”

“…Human Myenteric ganglia, in neuronal and glial cells, circular muscular layer in muscular cells and nerve fibers in the distal colon [3] Mucosal layer and enteric ganglia in the colon [21] Myenteric ganglia located in the sigmoid colon [22] The whole colonic wall [18,23] The wall of stomach: in gastric glands under physiological condition, parietal cells in the gastric body, stromal cells of gastric pylorus and in tumor cells located in the stomach [24,25] Rhesus monkey Esophagus: stratified squamous epithelial (SSE) cells bordering the lamina propria [26] Stomach: Chief and parietal cells of gastric glands Small intestine: cells in the lamina propria and enteroendocrine cells Mouse Mucosal layer of the small intestine [27] Zebrafish in the intestinal epithelium and muscularis externa layer serosa layer, or goblet cells [28] Investigations conducted on rodents have described that NRG1 in the peripheral nervous system participates in Schwann cells differentiation, axonal preservation and may show neuroprotective activity affecting survivability and regeneration of Schwann cells in rats [29,30]. Moreover, it is known that NRG1 enhances muscle re-innervation [31], affects the neurotransmitter receptors and ensures the proper functioning of peripheral synapses [32].…”

“…Regarding the innervation of the GI tract, it is known that NRG1 plays a key role in the development of the enteric nervous system (ENS), which has been confirmed by studies conducted on mice [ 33 , 34 ] and zebrafish [ 28 ]. In turn, observations conducted on humans have indicated that NRG1 is involved in pathological processes connected with intestinal diseases resulting from incorrect organization of the enteric ganglia, including Hirschsprung’s disease and diverticular disease [ 18 , 22 , 35 ].…”

Nicotinic Acetylcholine Receptor Involvement in Inflammatory Bowel Disease and Interactions with Gut Microbiota

“…In autoimmune ganglionopathies where autoantibodies against the α3 subunit are produced, gross ANS dysfunction occurs [55]. Similarly, patients with megacystis microcolon intestinal hypoperistalsis syndrome show significantly decreased expression of the α3 subunit [56], and patients with diverticular disease show decreased β4 subunit mRNA expression in the myenteric plexus [53]. These studies indicate an essential role of α3-containing nAChRs in the gut-brain axis.…”

“…Circular and longitudinal muscles of the gut wall, submucosa, epithelia, stomach, small and large intestines, colon [37,39,52,53] a Subunits detected by molecular biology techniques; b nAChR subtypes detected by functional assays; c rodent; d guinea pig; e human; f probable functional expression; * denotes the potential presence of other subunits.…”