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Review
. 2023 Feb 27;24(5):4602.
doi: 10.3390/ijms24054602.

Update on the Pathogenesis of the Hirschsprung-Associated Enterocolitis

Shuai Li  1 , Yichun Zhang  1 , Kang Li  1 , Yuan Liu  1 , Shuiqing Chi  1 , Yong Wang  1 , Shaotao Tang  1
Affiliations
Review

Update on the Pathogenesis of the Hirschsprung-Associated Enterocolitis

Shuai Li et al. Int J Mol Sci. .

Abstract

Despite the significant progress that has been made in terms of understanding the pathophysiology and risk factors of Hirschsprung-associated enterocolitis (HAEC), the morbidity rate has remained unsatisfactorily stable, and clinical management of the condition continues to be challenging. Therefore, in the present literature review, we summarized the up-to-date advances that have been made regarding basic research on the pathogenesis of HAEC. Original articles published between August 2013 and October 2022 were searched in a number of databases, including PubMed, Web of Science, and Scopus. The keywords "Hirschsprung enterocolitis", "Hirschsprung's enterocolitis", "Hirschsprung's-associated enterocolitis", and "Hirschsprung-associated enterocolitis" were selected and reviewed. A total of 50 eligible articles were obtained. The latest findings of these research articles were grouped into gene, microbiome, barrier function, enteric nervous system, and immune state categories. The present review concludes that HAEC is shown to be a multifactorial clinical syndrome. Only deep insights into this syndrome, with an accrual of knowledge in terms of understanding its pathogenesis, will elicit the necessary changes that are required for managing this disease.

Keywords: Hirschsprung disease (HSCR); Hirschsprung-associated enterocolitis (HAEC); enterocolitis; pathogenesis; review.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Flow chart: literature review.
Figure 2
Figure 2
Pathogenesis advances in genes, intestinal microflora, and mucosal barrier. p.H187Q in the Oncostatin-M receptor (OSMR) gene is a susceptible variant of HAEC, which promotes inflammation by activating the OSM-OSMR axis. Decreased integrin beta-2 (ITGB2) mRNA expression is negatively correlated with the incidence and severity of HAEC. Overgrowth and reduced diversity of intestinal bacteria lead to increased release of inflammatory factors, which leads to intestinal dysmotility, which in turn leads to further bacterial overgrowth. Epithelial cells produce less secretory phospholipase A2 (sPLA2), which reduces the inhibition of bacteria and promotes bacterial overgrowth. Lipopolysaccharide (LPS) produced by bacteria can promote the development of HAEC, while exclusive breastfeeding regulates the gut microbiome in such a way that LPS production is reduced. Short-chain fatty acids (SCFAs) produced by bacteria are reduced, and their composition is altered, impairing the function of maintaining mucosal integrity. The expressions of TFF3, SPDEF, and KLF4 are significantly down-regulated, leading to the decrease in goblet cells (GCs) and the secretion of neutral and acidic mucins, which lead to the weakening of the mucosal barrier function. The expression of glial cell line-derived neurotrophic factor (GDNF) co-receptor and GDNF family receptor alpha-1 (GFRα1) is decreased, and the colonization of neuronal progenitor cells in the intestine is impaired, affecting ENS development, resulting in GCs dysplasia, and abnormal mucin production and storage. The structure of the tight-junction protein is damaged, and its composition is changed, which impairs its function of maintaining the mucosal barrier integrity. Escherichia coli JM83 stimulates NF-κB through TLR4 and MyD88, and through NF-κB/p-p38 signal transduction, F-actin protein density is significantly reduced, IL-10, TNF-α, TGF-β increase, leading to intestinal mucosal damage and promoting the development of HAEC. TREK-1 and K(ATP) channels are reduced, leading to barrier dysfunction. Increased expressions of PAR-1 and PAR-2 lead to excessive local release of PAR-activating protease, which leads to inflammatory responses and impairs barrier function.
Figure 3
Figure 3
Pathogenesis advances in ENS. With a low cholinergic innervation degree in colon mucosa, Th17 cells and Treg cells regulate intestinal inflammatory response through the production of IL-17 and IL-23, promoting the development of HAEC. The decreased expression of caveolin-1 (Cav-1) results in the overactivation of inducible NO synthase (iNOS), which produces NO to promote inflammatory response while decreasing the inhibition of endothelial NOS (eNOS) on inflammatory response. The increased expression of NOS interacting protein (NOSIP) promotes inflammatory response and destroys the mucosal barrier by inhibiting NO production of neuronal NOS (nNOS) and eNOS. Interstitial cells of Cajal (ICCs) lose the c-Kit phenotype, resulting in impaired pacemaker function and intestinal motility. Cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) are two key enzymes in the synthesis of hydrogen sulfide from L-cysteine. The decreased expression of CBS and CSE reduces gastrointestinal peristalsis and promotes the inflammatory response.
Figure 4
Figure 4
Pathogenesis advances in immunity. The number of common lymphocyte progenitor populations and, therefore, T cells and B cells decrease significantly, resulting in reduced immunoglobulin, which is actively transported to the mucosal surface by polymerized immunoglobulin receptors (pIgR) in the form of dimers to maintain the intestinal microenvironment balance and normal function. pIgR is also reduced, which together leads to intestinal microenvironment disturbances and bacterial overgrowth. Increased Th17 cells produce more IL-17 and promote the intestinal inflammatory response. On one hand, LPS produced by bacteria activates M1 macrophages through the TLR4 pathway, and M1 macrophages produce TNF-α, which inhibits c-Kit expression in ICC through the NF-κB/miR-221 pathway, leading to intestinal motility disorders, which further leads to the accumulation and overgrowth of intestinal bacteria. 4-octyl itaconate (OI) reduces the production of proinflammatory factors and promotes ICC phenotypic recovery by inhibiting macrophage activation. LPS, on the other hand, induces the up-regulation of miR-132/-212, activates inflammasome NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) by inhibiting the expression of sirtuin 1 (Sirt1), promotes cell pyroptosis, and then promotes the occurrence and development of HAEC. Acetylcholine acts on α7 nicotinic acetylcholine receptor (α7nAChR) on the surface of macrophages, inhibits the activation of macrophages, activates the anti-inflammatory pathway of JAK2-STAT3 and suppresses the inflammatory pathway of NF-κB. Acetylcholine in HAEC is reduced, and the above anti-inflammatory effects are weakened. Exosome miR-18a-5p down-regulates RAR-related orphan receptor A (RORA), activates the SIRT1/NF-κB signaling pathway, induces excessive inflammatory response, and thus promotes the development of HAEC.
Figure 5
Figure 5
Updated pathogenesis of HAEC.
See this image and copyright information in PMC

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