Nerves Make the Bowel Happy, Even When the Enteric Nervous System Is Missing!

Heuckeroth, Robert O.

doi:10.1016/j.jcmgh.2021.05.012

Cited by 2 publications

(3 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, our group discovered that the lack of mucosal cholinergic innervation in the distal colon of HSCR patients was associated with increased inflammatory immune cell status and enterocolitis in a prospective study set up. [17,37,38].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…[30][31][32][33][34][35][36] Recently, our group discovered that the lack of mucosal cholinergic innervation in the distal colon of HSCR patients was associated with increased inflammatory immune cell status and enterocolitis in a prospective study setup. 17,37,38 Therefore, the aim of the present study was to assess-in a large cohort of patients and extended follow-up timewhether the mucosal fiber phenotype is associated with enterocolitis in a retrospective three-center cohort study including HSCR patients from the past 20 years. Compared with our previous data, the current study includes the analysis of conserved patient tissue from local pathology units and extended clinical parameter analysis.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Associations of Mucosal Nerve Fiber Innervation Density with Hirschsprung-Associated Enterocolitis: A Retrospective Three-Center Cohort Study

Moesch

Usemann²,

Bruder

et al. 2022

Eur J Pediatr Surg

View full text Add to dashboard Cite

Hirschsprung disease (HSCR) is a congenital intestinal neurodevelopmental disorder characterized by the absence of enteric ganglion cells in the distal colon. Although Hirschsprung-associated enterocolitis (HAEC) is the most frequent life-threatening complication in HSCR, to date reliable biomarkers predicting the likelihood of HAEC are yet to be established. We established a three-center retrospective study including 104 HSCR patients surgically treated between 1998–2019. Patient-derived cryo- or paraffin-preserved colonic tissue at surgery was analyzed via beta III tubulin immunohistochemistry. We subsequently determined extrinsic mucosal nerve fiber density in resected rectosigmoid specimens and classified HSCR patients accordingly into nerve fiber-high or fiber-low groups. We compared the distribution of clinical parameters obtained from medical records between the fiber-high (n=36) and fiber-low (n=68) patient groups. We assessed the association between fiber phenotype and enterocolitis using univariate and multivariate logistic regression adjusted for age at operation. Enterocolitis was more prevalent in patients with sparse mucosal nerve fiber innervation (fiber-low phenotype, 87%) compared to the fiber-high phenotype (13%; p=0.002). In addition, patients developing enterocolitis had a younger age at surgery (3 months versus 7 months; p=0.016). In the univariate analysis, the odds for enterocolitis development in the fiber-low phenotype was 5.26 (95% CI 1.67–16.59; p=0.005) and 4.01 (95% CI 1.22–13.17; p=0.022) when adjusted for age. Here we showed that HSCR patients with a low mucosal nerve fiber innervation grade in the distal aganglionic colon have a higher risk of developing HAEC. Consequently, histopathologic analysis of the nerve fiber innervation grade could serve as a novel sensitive prognostic marker associated with the development of enterocolitis in HSCR patients.

show abstract

Section: Accepted Manuscriptmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Associations of Mucosal Nerve Fiber Innervation Density with Hirschsprung-Associated Enterocolitis: A Retrospective Three-Center Cohort Study

Moesch

Usemann²,

Bruder

et al. 2022

Eur J Pediatr Surg

View full text Add to dashboard Cite

show abstract

“…Previous work from our group uncovered a before-unknown correlation between the mucosal fiber innervation density and the onset of enterocolitis in HSCR patients ( 4 ). HSCR patients showing prominent colonic mucosal AChE + nerve fibers (fiber-high) had decreased inflammatory cytokines and TH17 T cells as well as lower incidence of enterocolitis development compared to HSCR patients with only sparse mucosal innervation (fiber-low) ( 4 , 37 ). AChE + nerve fibers were closely associated with bipolar tissue-resident macrophages and their presence correlated with lower macrophage-dependent expression of the TH17-promoting cytokine IL-23.…”

Section: Introductionmentioning

confidence: 96%

Cholinergic Signaling Attenuates Pro-Inflammatory Interleukin-8 Response in Colonic Epithelial Cells

et al. 2022

View full text Add to dashboard Cite

Infants affected by Hirschsprung disease (HSCR), a neurodevelopmental congenital disorder, lack ganglia of the intrinsic enteric nervous system (aganglionosis) in a variable length of the colon, and are prone to developing severe Hirschsprung-associated enterocolitis (HAEC). HSCR patients typically show abnormal dense innervation of extrinsic cholinergic nerve fibers throughout the aganglionic rectosigmoid. Cholinergic signaling has been reported to reduce inflammatory response. Consequently, a sparse extrinsic cholinergic innervation in the mucosa of the rectosigmoid correlates with increased inflammatory immune cell frequencies and higher incidence of HAEC in HSCR patients. However, whether cholinergic signals influence the pro-inflammatory immune response of intestinal epithelial cells (IEC) is unknown. Here, we analyzed colonic IEC isolated from 43 HSCR patients with either a low or high mucosal cholinergic innervation density (fiber-low versus fiber-high) as well as from control tissue. Compared to fiber-high samples, IEC purified from fiber-low rectosigmoid expressed significantly higher levels of IL-8 but not TNF-α, IL-10, TGF-β1, Muc-2 or tight junction proteins. IEC from fiber-low rectosigmoid showed higher IL-8 protein concentrations in cell lysates as well as prominent IL-8 immunoreactivity compared to IEC from fiber-high tissue. Using the human colonic IEC cell line SW480 we demonstrated that cholinergic signals suppress lipopolysaccharide-induced IL-8 secretion via the alpha 7 nicotinic acetylcholine receptor (a7nAChR). In conclusion, we showed for the first time that the presence of a dense mucosal cholinergic innervation is associated with decreased secretion of IEC-derived pro-inflammatory IL-8 in the rectosigmoid of HSCR patients likely dependent on a7nAChR activation. Owing to the association between IL-8 and enterocolitis-prone, fiber-low HSCR patients, targeted therapies against IL-8 might be a promising immunotherapy candidate for HAEC treatment.

show abstract

Nerves Make the Bowel Happy, Even When the Enteric Nervous System Is Missing!

Cited by 2 publications

References 5 publications

Associations of Mucosal Nerve Fiber Innervation Density with Hirschsprung-Associated Enterocolitis: A Retrospective Three-Center Cohort Study

Associations of Mucosal Nerve Fiber Innervation Density with Hirschsprung-Associated Enterocolitis: A Retrospective Three-Center Cohort Study

Cholinergic Signaling Attenuates Pro-Inflammatory Interleukin-8 Response in Colonic Epithelial Cells

Contact Info

Product

Resources

About