Infantile hypertrophic pyloric stenosis (IHPS): A study of its pathophysiology utilizing the newborn <i>hph-1</i> mouse model of the disease

Neurogastroenterology Motil

Pan

et al. 2017

Section: Discussionsupporting

confidence: 57%

“…In the gastrointestinal tract this pathway is physiologically required and reduced ROCK‐2 activation is associated with dysmotility . We previously showed that ROCK‐2 is a key regulator of gastropyloric motor function early in life and the tissue protein content is reduced in newborn rodents …”

Section: Discussionmentioning

confidence: 99%

The newborn rat gastric emptying rate is volume and not developmentally dependent

Ferreira

Neurogastroenterology Motil

Pan

et al. 2017

“…The increased sphincter tone in infants with this condition is likely related to reduced pyloric tissue neuronal nitric oxide (NO) synthase (nNOS) expression (1) and the resulting lower NO generation (25,36,44). In the rodent model of this disease, we previously showed that increased pyloric sphincter tone is transiently present (47).…”

mentioning

confidence: 99%

Gastric and pyloric sphincter muscle function and the developmental-dependent regulation of gastric content emptying in the rat

Sobchak

Fajardo

American Journal of Physiology-Gastrointestinal and Liver Physi

et al. 2016

Self Cite

Feeding intolerance is a common issue in the care of preterm neonates. The condition manifests as delayed emptying of gastric contents and represents a therapeutic challenge, since the factors accounting for its manifestations are unknown. The main goal of this study was to comparatively investigate the age-related function of rat gastric and pyloric smooth muscle and their putative regulators. We hypothesized that a reduced gastric muscle contraction potential early in life contributes to the delayed gastric emptying of the newborn. Newborn and adult rat gastric (fundus) and pyloric sphincter tissues were comparatively studied in vitro. Shortening of the tissue-specific dissociated smooth muscle cell was evaluated, and expression of the key regulatory proteins Rho-associated kinase 2 and myosin light chain kinase was determined. Gastric and pyloric smooth muscle cell shortening was significantly greater in the adult than the respective newborn counterpart. Expression of myosin light chain kinase and Rho-associated kinase 2 was developmentally regulated and increased with age. Pyloric sphincter muscle expresses a higher neuronal nitric oxide synthase and phosphorylated vasodilator-stimulated phosphoprotein content in newborn than adult tissue. Compared with later in life, the newborn rat gastropyloric muscle has a Ca(2+)-related reduced potential for contraction and the pyloric sphincter relaxation-dependent modulators are overexpressed. To the extent that these rodent data can be extrapolated to humans, the delayed gastric emptying in the newborn reflects reduced stomach muscle contraction potential, as opposed to increased pyloric sphincter tone.

“…For instance, idiopathic hypertrophic pyloric stenosis is present in 1–2 week old hph-1 mice, but completely regresses in adult life8. BH4 deficiency has also been linked to the idiopathic human condition, hypertrophic pyloric stenosis, through a mechanism based on nitric oxide synthase-dependent pyloric sphincter regulation8. Idiopathic hypertrophic pyloric stenosis in humans solely manifests in infants and if left untreated, the condition spontaneously resolves9.…”

mentioning

confidence: 99%

Intestinal microbiota as a tetrahydrobiopterin exogenous source in hph-1 mice

Belik

Arning³

et al. 2017

Sci Rep

Self Cite

Tetrahydrobiopterin (BH4) is a cofactor of a number of regulatory enzymes. Although there are no known BH4 exogenous sources, the tissue content of this biopterin increases with age in GTP cyclohydrolase 1-deficient hyperphenylalaninemia-1 (hph-1) mice. Since certain bacteria are known to generate BH4, we hypothesize that generation of this biopterin by the intestinal microbiota contributes to its tissue increase in hph-1 adult mice. The goal of this study was to comparatively evaluate hph-1 mice and wild-type C57Bl/6 controls for the presence of intestinal BH4-producing bacteria. Newborn and adult mice fecal material was screened for 6-pyruvoyltetrahydropterin synthase (PTPS-2) an enzyme only present in BH4-generating bacteria. Adult, but not newborn, wild-type control and hph-1 mouse fecal material contained PTPS-2 mRNA indicative of the presence of BH4-generating bacteria. Utilizing chemostat-cultured human fecal bacteria, we identified the PTPS-2-producing bacteria as belonging to the Actinobacteria phylum. We further confirmed that at least two PTPS-2-producing species, Aldercreutzia equolifaciens and Microbacterium schleiferi, generate BH4 and are present in hph-1 fecal material. In conclusion, intestinal Actinobacteria generate BH4. This finding has important translational significance, since manipulation of the intestinal flora in individuals with congenital biopterin deficiency may allow for an increase in total body BH4 content.