Colitis-Induced Small Intestinal Hypomotility Is Dependent on Enteroendocrine Cell Loss in Mice.

BACKGROUND & AIMS: The abdominal discomfort experienced by patients with colitis may be attributable in part to the presence of small intestinal dysmotility, yet mechanisms linking colonic inflammation with small-bowel motility remain largely unexplored. We hypothesize that colitis results in small intestinal hypomotility owing to a loss of enteroendocrine cells (EECs) within the small intestine that can be rescued using serotonergic-modulating agents. METHODS: Male C57BL/6J mice, as well as mice that overexpress (EECOVER) or lack (EECDEL) NeuroD1+ enteroendocrine cells, were exposed to dextran sulfate sodium (DSS) colitis (2.5% or 5% for 7 days) and small intestinal motility was assessed by 70-kilodalton fluorescein isothiocyanate-dextran fluorescence transit. EEC number and differentiation were evaluated by immunohistochemistry, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining, and quantitative reverse-transcriptase polymerase chain reaction. Mice were treated with the 5-hydroxytryptamine 4 agonist prucalopride (5 mg/kg orally, daily) to restore serotonin signaling. RESULTS: DSS-induced colitis was associated with a significant small-bowel hypomotility that developed in the absence of significant inflammation in the small intestine and was associated with a significant reduction in EEC density. EEC loss occurred in conjunction with alterations in the expression of key serotonin synthesis and transporter genes, including Tph1, Ddc, and Slc6a4. Importantly, mice overexpressing EECs revealed improved small intestinal motility, whereas mice lacking EECs had worse intestinal motility when exposed to DSS. Finally, treatment of DSS-exposed mice with the 5-hydroxytryptamine 4 agonist prucalopride restored small intestinal motility and attenuated colitis. CONCLUSIONS: Experimental DSS colitis induces significant small-bowel dysmotility in mice owing to enteroendocrine loss that can be reversed by genetic modulation of EEC or administering serotonin analogs, suggesting novel therapeutic approaches for patients with symptomatic colitis.

Bile acid profiles in adult patients with biliary atresia who achieve native liver survival after portoenterostomy.

Bile acids have received increasing attention as a marker of the long-term prognosis and a potential therapeutic target in patients with biliary atresia, which is a progressive disease of the hepatobiliary system. A detailed analysis of serum and urinary bile acid compositions was conducted to assess the characteristics of bile acid profiles and the correlation between bile acid profiles and liver fibrosis markers in adult patients with biliary atresia who achieved bilirubin normalization. Serum total bile acids and glucuronide-conjugated (glyco- and tauro-) cholic acids (GCA and TCA) and chenodeoxycholic acids (GCDCA and TCDCA) were significantly higher in patients with biliary atresia than in healthy controls, whereas unconjugated CA and CDCA showed no significant difference. There were no significant differences in CA to CDCA ratios and glycine-to-taurine-conjugated ratios. Urinary glycocholic acid 3-sulfate (GCA-3S) was significantly higher in patients with biliary atresia. Serum GCDCA showed a strong positive correlation with Mac-2 binding protein glycosylation isomer (M2BPGi). These results demonstrate that bile acid congestion persists into adulthood in patients with biliary atresia, even after cholestasis has completely improved after Kasai portoenterostomy. These fundamental data on bile acid profiles also suggest the potential value of investigating bile acid profiles in patients with biliary atresia.

Prednisolone administration monitored by postoperative stool color achieves high jaundice clearance after laparoscopic portoenterostomy for biliary atresia.

PURPOSE: Stool color (SC) for monitoring prednisolone use in biliary atresia (BA) patients after laparoscopic portoenterostomy (LPE) was reviewed. METHODS: Subjects were 47 post-LPE BA patients given a reducing dose course of intravenous prednisolone. The course started at 4 mg/kg/day and gradually reduced, ultimately reaching a final total dose (TD) of 31.5 mg/kg. Normal SC indicated a course could progress until finished and was repeated until jaundice clearance (JC) was achieved. Abnormal SC persisting for two consecutive courses was the absolute indication for redo or liver transplantation (LTx). RESULTS: JC was achieved in 38/47 (80.9%) LPE cases and 4/6 redos to give an overall JC rate (JCR) of 42/47 (89.4%). Outcomes after one course (n = 5; JCR: 80.0%; median TD: 30.0 mg/kg, interquartile range [IQR: 26.0-31.5]), two courses (n = 10; JCR: 90.0%; median TD: 62.5 mg/kg [IQR: 60.8-66.0]), three courses (n = 13; JCR: 92.3%; median TD: 90.0 mg/kg [IQR: 86.0-90.0]), four courses (n = 10; JCR: 80.0%; median TD: 120.0 mg/kg [IQR: 116.7-123.3]), five courses (n = 7; JCR: 100%; median TD: 156.0 mg/kg [IQR: 154.3-157.5]), six courses (n = 1; JCR: 100%; TD: 189.0 mg/kg), ten courses (n = 1; JCR: 100%; TD: 308 mg/kg). CONCLUSION: Indications for repeat prednisolone and timing of redo/LTx based on SC monitoring appeared effective based on high JCR and successful redo/LTx. LEVELS OF EVIDENCE: III.

Necrotizing enterocolitis, gut microbes, and sepsis.

Necrotizing enterocolitis (NEC) is a devastating disease in premature infants and the leading cause of death and disability from gastrointestinal disease in this vulnerable population. Although the pathophysiology of NEC remains incompletely understood, current thinking indicates that the disease develops in response to dietary and bacterial factors in the setting of a vulnerable host. As NEC progresses, intestinal perforation can result in serious infection with the development of overwhelming sepsis. In seeking to understand the mechanisms by which bacterial signaling on the intestinal epithelium can lead to NEC, we have shown that the gram-negative bacterial receptor toll-like receptor 4 is a critical regulator of NEC development, a finding that has been confirmed by many other groups. This review article provides recent findings on the interaction of microbial signaling, the immature immune system, intestinal ischemia, and systemic inflammation in the pathogenesis of NEC and the development of sepsis. We will also review promising therapeutic approaches that show efficacy in pre-clinical studies.

Human milk oligosaccharides reduce necrotizing enterocolitis-induced neuroinflammation and cognitive impairment in mice.

Necrotizing enterocolitis (NEC) is the leading cause of morbidity and mortality in premature infants. One of the most devastating complications of NEC is the development of NEC-induced brain injury, which manifests as impaired cognition that persists beyond infancy and which represents a proinflammatory activation of the gut-brain axis. Given that oral administration of the human milk oligosaccharides (HMOs) 2'-fucosyllactose (2'-FL) and 6'-sialyslactose (6'-SL) significantly reduced intestinal inflammation in mice, we hypothesized that oral administration of these HMOs would reduce NEC-induced brain injury and sought to determine the mechanisms involved. We now show that the administration of either 2'-FL or 6'-SL significantly attenuated NEC-induced brain injury, reversed myelin loss in the corpus callosum and midbrain of newborn mice, and prevented the impaired cognition observed in mice with NEC-induced brain injury. In seeking to define the mechanisms involved, 2'-FL or 6'-SL administration resulted in a restoration of the blood-brain barrier in newborn mice and also had a direct anti-inflammatory effect on the brain as revealed through the study of brain organoids. Metabolites of 2'-FL were detected in the infant mouse brain by nuclear magnetic resonance (NMR), whereas intact 2'-FL was not. Strikingly, the beneficial effects of 2'-FL or 6'-SL against NEC-induced brain injury required the release of the neurotrophic factor brain-derived neurotrophic factor (BDNF), as mice lacking BDNF were not protected by these HMOs from the development of NEC-induced brain injury. Taken in aggregate, these findings reveal that the HMOs 2'-FL and 6'-SL interrupt the gut-brain inflammatory axis and reduce the risk of NEC-induced brain injury.NEW & NOTEWORTHY This study reveals that the administration of human milk oligosaccharides, which are present in human breast milk, can interfere with the proinflammatory gut-brain axis and prevent neuroinflammation in the setting of necrotizing enterocolitis, a major intestinal disorder seen in premature infants.

Retroperitoneoscopic Pyeloplasty for Ureteropelvic Junction Obstruction in Children: Value of Robotic Assistance.

AIM: Retroperitoneal pyeloplasty (RP) for pediatric ureteropelvic junction obstruction (UPJO) performed using retroperitoneoscopy (retro-RP) or robotic assistance (robo-RP) were compared. METHODS: All subjects were Japanese, matched for age, weight, and RP diameters. All RP were performed in the lateral decubitus position at a single institute by the same team using identical protocols. Five independent surgeons were asked to score intraoperative video recordings for perceived difficulty of suturing (DOS; 5 = impossible; 4 = difficult; 3 = tedious; 2 = slow; 1 = easy) and rank RP as +1 if robo-RP appeared to be superior, 0 if they appeared to be the same, and -1 if robo-RP appeared to be inferior. RESULTS: Robo-RP performed 2018-2022 (n = 22) were matched with retro-RP performed 2011-2019 (n = 34). Mean overall operative times were similar (robo-RP: 305.2 ± 57.8 min versus retro-RP: 340.0 ± 117.9 min; p = 0.19), but securing the larger retroperitoneal space required for robo-RP took significantly longer; 50.8 ± 13.9 min versus 24.3 ± 9.6 min; p < 0.0001. Total anastomotic time (TAT) and TAT per suture were both significantly shorter for robo-RP (p < 0.0001). The coefficient of variation for time taken to place one suture was smaller for robo-RP than for retro-RP. DOS was lower for robo-RP with less variance (p < 0.01). Robo-RP had shorter drainage tube insertion, ambulated quicker postoperatively, and shorter hospitalization. Retro-RP had anastomotic complications; leaks (n = 2) and strictures (n = 2, requiring conventional open re-pyeloplasty). Robo-RP had no anastomotic complications and was ranked +1 unanimously. CONCLUSIONS: The RP anastomosis was quicker with less complications and more precise with robotic assistance in matched patients under similar circumstances. Should RP be indicated, robo-RP is recommended. LEVEL OF EVIDENCE: III.

Biopsy Diagnosis of Hirschsprung's Disease Using a Single Excisional Biopsy Based on the Anorectal Line.

INTRODUCTION: A biopsy protocol for diagnosing Hirschsprung's disease (HD) in children using the anorectal line (ARL). MATERIALS AND METHODS: The ARL was adopted for diagnosing HD in 2016 using two excisional submucosal rectal biopsies performed at different levels, sequentially; the first just above the ARL and the second, further proximal (2-ARL). Currently, only the first-level biopsy is performed (1-ARL) and examined intraoperatively. Management was observation if normoganglionic, pull-through if aganglionic, and a second-level biopsy if hypoganglionic. Hypoganglionosis was considered physiologic if the second-level biopsy was normoganglionic and pathologic if hypoganglionic. Colon caliber change and bowel obstructive symptoms reflect the severity of hypoganglionosis. RESULTS: For 2-ARL (n = 54), results were: normoganglionosis (n = 31/54; 57.4%), aganglionosis (n = 19/54; 35.2%), and hypoganglionosis (n = 4/54; 7.4%); physiologic (n = 3/54; 5.6%) and pathologic (n = 1/54; 1.9%). Normoganglionosis and aganglionosis were always duplicated in 2-ARL (kappa = 1.0). For 1-ARL (n = 36), results were: normoganglionosis (n = 17/36; 47.2%), aganglionosis (n = 17/36; 47.2%), and hypoganglionosis (n = 2/36; 5.6%). Second-level biopsies were normoganglionic (physiologic: n = 1) and hypoganglionic (pathologic: n = 1). All normoganglionic cases, except one, resolved conservatively. All aganglionic cases had pull-through with HD confirmed on histopathology. Both pathologic hypoganglionic cases had caliber change and severe obstructive symptoms as definitive indications for pull-through with hypoganglionosis of the entire rectum confirmed on histopathology. Physiologic hypoganglionic cases were observed and currently have regular defecation. CONCLUSION: Because the ARL is an objective functional, neurologic, and anatomic demarcation, normoganglionosis and aganglionosis can be diagnosed accurately with a single excisional biopsy. Only hypoganglionosis requires a second-level biopsy.

Native liver survivors of portoenterostomy for biliary atresia with excellent outcome: redefining "successful" portoenterostomy.

PURPOSE: Native liver survivors (NLS) after portoenterostomy (PE) for biliary atresia (BA) with normal biomarkers defined as total bilirubin (T-Bil), aspartate aminotransferase (AST)/alanine aminotransferase (ALT) for liver function (LF), cholinesterase (ChE), platelet count (PC), and absence of portal hypertension (PHT) were reviewed to redefine "successful" PE. METHODS: 92 post-PE BA patients were classified as NLS-1: normal biomarkers, PHT (-); NLS-2: at least one abnormal biomarker, PHT (-); NLS-3: normal biomarkers, PHT ( +); NLS-4: abnormal biomarkers, PHT ( +) and reviewed for a maximum 32 years. RESULTS: As of June 2022, 55/92 (59.8%) had received liver transplants and 37/92 (40.2%) were NLS. NLS patients were classified as excellent outcome (EO): NLS-1 (n = 10; 27.0%) or non-EO: NLS-2: (n = 8; 21.6%), NLS-3: (n = 6; 16.2%), and NLS-4: (n = 13; 35.1%). Compared with non-EO, EO had PE earlier (50.5 versus 65 days; not significant; p = 0.08), significantly earlier onset of symptoms (13 days versus 32 days; p = 0.01) and significantly shorter jaundice-clearance (JC; 34.5 days versus 56.0 days; p < 0.001). Durations of follow-up were similar: 13 years in EO, 18.5 years in NLS-2, 20 years in NLS-3, and 15 years in NLS-4. CONCLUSION: Incidence of "successful" PE or EO is low and correlated with early onset of symptoms and quicker JC.

Quality of life after type-A esophageal atresia surgery: changes over time and effect of pre-anastomotic elongation.

AIM: To assess mid-/long-term postoperative quality of life (QOL) of esophageal atresia (EA) patients. METHODS: Modified gastrointestinal quality-of-life index surveys were administered to postoperative EA patients who were at least 7 years old at evaluation to assess three topics about general lifestyle (GL), five topics about EA, and four topics about mental health (MH). For MH, caregivers were also interviewed, but separately. Subjects were divided according to age: children (7-12 years old), teenagers (13-19), and adults (20 and over) and compared according to Foker or Kimura elongation (FK) or bougienage stretching (BS). RESULTS: There were 22 patients evaluated. Responses for GL, EA, and MH did not differ significantly between age groups, but MH responses by caregivers for subjects who were children or teenagers scored significantly lower than responses they made themselves. For primary esophageal elongation technique (PET), age at esophagoesophagostomy was significantly higher in FK. Despite FK scoring 15.1 versus 12.4 for BS during EA evaluation, this difference was not statistically significant. CONCLUSION: Changes in QOL responses according to age were unremarkable. However, discrepancies in MH indicate that subjects felt better than their caregivers thought. PET did not appear to influence QOL.

Changes in postoperative quality of life of pediatric total colonic aganglionosis patients: effect of pull-through technique.

AIM: To assess mid-/long-term quality of life (QOL) of total colonic aganglionosis (TCA) patients. METHODS: Modified pre-existing QOL assessment tools for general lifestyle (GL), bowel function (BF), and mental health (MH) were administered to postoperative TCA patients from five institutions, who were at least 7 years old to compare Duhamel (with pouch) and Swenson/Soave (without pouch) techniques between children (Ch 7-12 years old), teenagers (Tn 13-19), and adults (Ad 20 and over). For MH, caregivers were also interviewed, but separately. Maximum scores were 12 for GL/MH and 18 for BF. RESULTS: There were 32 subjects. GL and BF scores increased significantly from Ch (GL 4.8 ± 2.5, BF: 11.3 ± 4.6) to Tn (GL 7.8 ± 2.6, BF 16.2 ± 3.0); scores for MH did not change significantly. Mean caregiver MH scores were significantly lower than mean subject MH scores for all age groups (subject scores: 10.1, 10.7, 10.7 versus caregiver scores: 6.8, 7.8, 8.1 for Ch, Tn, Ad, respectively). PT technique/presence of a pouch did not influence the incidence of enterocolitis or QOL scores. CONCLUSION: MH responses showed subjects felt better than caregivers believed. This discrepancy could cause conflict despite steadily improving GL/BF. QOL was unaffected by PT technique/presence of a pouch.

Biochemical Evaluation of Laparoscopic Portoenterostomy for Treating Biliary Atresia and Redo for Failed Portoenterostomy.

Background: Postoperative outcomes of portoenterostomy (PE) and redo-PE were evaluated using selected biochemical markers (SBM) and biochemical status categories (BSC). Methods: Subjects were 70 consecutive PE performed for biliary atresia. SBM were aspartate aminotransferase (AST)/alanine aminotransferase (ALT), cholinesterase (ChE), and platelet count (PLT) assessed at 1, 2, 3, 6, and 12 months, and thence, annually for a maximum of 10 years. BSC were as follows: all SBM normal (N-SBM), normal AST/ALT (N-SLT), normal ChE (N-ChE), normal PC (N-PLT), all abnormal (A-SBM), abnormal AST/ALT (A-SLT), abnormal ChE (A-ChE), and abnormal PC (A-PLT). Subjects achieving jaundice clearance (JC) and surviving with native livers (SNL) also had gamma glutamyl transpeptidase assessed. Redo-PE indicated for failed PE was assessed postoperatively using the same SBM/BSC protocol. Results: PE were laparoscopic (LPE; n = 40) or open (OPE; n = 30). Mean age/weight at PE and duration of follow-up were similar. For JC, LPE = 34/40 (85.0%) and OPE = 22/30 (73.3%); P = .23. For SNL, LPE = 29/40 (72.5%) and OPE = 16/30 (53.3%); P = .10. LPE and OPE were similar for SBM/BSC, except for a single significant increase in ALT in OPE at 6 months. Redo-PE was performed 17-180 days (mean 67.1 days) after primary PE. AST was significantly increased at the last preredo assessment 3 months after primary PE; P < .05. After redo, AST decreased and SBM/BSC results were equivalent to nonredo subjects. Conclusion: Postoperative biochemical data for all PE cases were comparable; redo-PE would appear to be viable for restoring SBM, and AST could be valuable as a single marker of deterioration in redo cases.

The Outcome of Patients With Cystic Biliary Atresia With Intact Proximal Hepatic Ducts Following Hepatic-Cyst-Jejunostomy.

OBJECTIVES: To determine the outcomes of patients with cystic biliary atresia by correlating the anatomy of the hepatic ducts with the choice of biliary reconstruction surgery. BACKGROUND: The Kasai hepatoportoenterostomy (Kasai) is the initial surgical procedure offered to most patients with biliary atresia. In contrast, a hepatic-cyst-jejunostomy has been reported to be effective in patients with the cystic form of biliary atresia. METHODS AND RESULTS: We performed an international multicenter retrospective review. Two hundred eighty-seven patients were included, and 33 cases of cystic biliary atresia were identified. Outcomes were the serum total bilirubin level 3 months post-surgery and native liver survival at 2 years of age and were compared between cases who received the Kasai versus hepatic-cyst-jejunostomy in correlation to the anatomy of proximal hepatic ducts. The patients were categorized into 3 anatomical groups: patent intact hepatic ducts (n = 10), patent hypoplastic hepatic ducts (n = 13), and obliterated hepatic ducts (n = 10). All 10 patients with patent intact hepatic duct group underwent hepatic-cyst-jejunostomy, and 9 experienced bile drainage and native liver survival. Among the 13 patients with hypoplastic hepatic ducts, 11 underwent the Kasai procedure, and 9 had bile drainage, whereas 2 underwent hepatic-cyst-jejunostomy, and one survived with the native liver. All of the patients with obliterated hepatic ducts underwent the Kasai procedure; 5 established biliary drainage and survived with the native liver. Of 5 who did not drain, 3 underwent liver transplantation. CONCLUSIONS: In patients with cystic biliary atresia, the subset with a connection between cyst and intrahepatic bile ducts via intact proximal hepatic ducts had favorable clinical outcomes following hepatic-cyst-jejunostomy.