Intestinal Microbiome

- The human gut dominated by Firmicutes and Bacteroidetes, with proteobacteria also
present.
- The normal gut flora is in a dynamic balance, crucial for the intestine's stability and proper
functioning.
Animal Experimental

 Mice with neural crest conditional deletion of endothelin receptor B (EdnrB)

exhibited impaired mucosal barrier function and developed ecological
dysregulation prior to the onset of HAEC, as evidenced by decreased levels of
luminal secretory phospholipase A2 (sPLA2) and increased intestinal invasion by
Escherichia coli prior to HAEC and death.
Animal Experimental

 Proportion of fecal bacteria in HAEC model mice increased in the case of

Akkermansia and decreased in the case of Bacteroidetes, and that the genera with
reduced abundance in HAEC were Dysgonomonas and Clostridium cluster XIVa,
suggesting that Akkermansia may contribute to the development of HAEC,
whereas Bacteroidetes, Dysgonomonas, and Clostridium cluster XIVa may exert a
protective effect.
 It has been shown that the abundance of Veillonella parvula (VP) in intestinal
microorganisms is higher in patients with HAEC compared with patients with
HSCR
Animal Experimental

 VP exerted proinflammatory effects by increasing the concentration of inflammatory

cytokines and impairing intestinal motility in the colon, and VP-derived
lipopolysaccharide (LPS) was used to establish a mouse model of inflammation
wherein LPS both elicited a markedly enhanced paracellular permeability of mouse
colonic epithelial cells and activated macrophages via the Toll-like receptor 4
(TLR4) pathway.
 Tumor necrosis factor-alpha (TNF-alpha) from polarized macrophages was found to
impair the pacemaker function of interstitial cells of Cajal (ICCs), which
subsequently inhibited intestinal motility, and intestinal dysmotility exacerbated
intestinal dysbiosis, in turn promoting the development of HAEC.
 Cultured E. coli, Enterococcus spp., Bacillus, Proteus mirabilis, and Clostridium spp.
in the mesenteric lymph nodes, spleen, liver, kidneys, and lungs of HACE-modeled
rats, and found that E. coli had the highest ectopic rate.
Both animal and clinical studies have
similar biomolecular explanation
Summary Animal Experimental

 Several studies have investigated the role of gut microbiota in the development of
Hirschsprung's-associated enterocolitis (HAEC). Pierre found that mice lacking the
endothelin receptor B (EdnrB) showed impaired mucosal barrier function and
dysregulation of gut bacteria prior to HAEC onset. Cheng observed changes in
bacterial proportions, suggesting Akkermansia may contribute to HAEC development,
while Bacteroidetes, Dysgonomonas, and Clostridium cluster XIVa might have
protective effects. VP abundance was found to be higher in HAEC patients compared
to those with Hirschsprung's disease. Zhan discovered that VP exerted
proinflammatory effects through increased inflammatory cytokines and impaired
intestinal motility. Mitroudi cultured various bacteria in HACE-modeled rats, with E.
coli showing the highest ectopic rate. Arnaud observed higher abundance of
proinflammatory bacteria in the aganglionic rectosigmoid lumen. However, the exact
relationship between these bacteria and the onset of HAEC remains unclear.
Summary Clinical Studies

 In summary, various studies have explored the role of gut microbiota in the
development of Hirschsprung's-associated enterocolitis (HAEC). Some research
indicates that certain pathogenic bacteria, such as Clostridium difficile and
Proteobacteria, may be associated with HAEC risk. Differences in gut microbial
diversity have been observed between patients with HAEC and those with
Hirschsprung's disease (HSCR), but the causal relationship is not yet clear.
Additionally, changes in short-chain fatty acids (SCFAs) production by gut bacteria
have been linked to HAEC development, impacting colonic mucosal integrity.
Metabolite abnormalities found in HAEC patients suggest possible dysregulation of
gut microbes, leading to colonic ecological dysregulation and HAEC. Furthermore, a
study suggested that exclusive breastfeeding may regulate gut microbiota and reduce
the risk of HAEC in HSCR patients by lowering Gram-negative bacteria and
endotoxin levels. More research is needed to understand the complex interactions
between gut microbiota and HAEC development.