Evaluation of pediatric patients for intestinal transplantation in the modern era.

OBJECTIVES: To review recent evaluations of pediatric patients with intestinal failure (IF) for intestinal transplantation (ITx), waiting list decisions, and outcomes of patients listed and not listed for ITx at our center. METHODS: Retrospective chart review of 97 patients evaluated for ITx from January 2014 to December 2021 including data from referring institutions and protocol laboratory testing, body imaging, endoscopy, and liver biopsy in selected cases. Survival analysis used Kaplan-Meier estimates and Cox proportional hazards regression. RESULTS: Patients were referred almost entirely from outside institutions, one-third because of intestinal failure-associated liver disease (IFALD), two-thirds because of repeated infective and non-IFALD complications under minimally successful intestinal rehabilitation, and a single patient because of lost central vein access. The majority had short bowel syndrome (SBS). Waiting list placement was offered to 67 (69%) patients, 40 of whom for IFALD. The IFALD group was generally younger and more likely to have SBS, have received more parenteral nutrition, have demonstrated more evidence of chronic inflammation and have inferior kidney function compared to those offered ITx for non-IFALD complications and those not listed. ITx was performed in 53 patients. Superior postevaluation survival was independently associated with higher serum creatinine (hazard ratio [HR] 15.410, p = 014), whereas inferior postevaluation survival was associated with ITx (HR 0.515, p = 0.035) and higher serum fibrinogen (HR 0.994, p = 0.005). CONCLUSIONS: Despite recent improvements in IF management, IFALD remains a prominent reason for ITx referral. Complications of IF inherent to ITx candidacy influence postevaluation and post-ITx survival.

Maternal Obesogenic Diet Attenuates Microbiome-Dependent Offspring Weaning Reaction with Worsening of Steatotic Liver Disease.

The mechanisms by which maternal obesity increases the susceptibility to steatotic liver disease in offspring are incompletely understood. Models using different maternal obesogenic diets (MODEs) display phenotypic variability, likely reflecting the influence of timing and diet composition. This study compared three maternal obesogenic diets using standardized exposure times to identify differences in offspring disease progression. This study found that the severity of hepatic inflammation and fibrosis in the offspring depends on the composition of the maternal obesogenic diet. Offspring cecal microbiome composition was shifted in all MODE groups relative to control. Decreased α-diversity in some MODE offspring with shifts in abundance of multiple genera were suggestive of delayed maturation of the microbiome. The weaning reaction typically characterized by a spike in intestinal expression of Tnfa and Ifng was attenuated in MODE offspring in an early microbiome-dependent manner using cross-fostering. Cross-fostering also switched the severity of disease progression in offspring dependent on the diet of the fostering dam. These results identify maternal diet composition and timing of exposure as modifiers in mediating transmissible changes in the microbiome. These changes in the early microbiome alter a critical window during weaning that drives susceptibility to progressive liver disease in the offspring.

Maternal obesogenic diet regulates offspring bile acid homeostasis and hepatic lipid metabolism via the gut microbiome in mice.

Mice exposed in gestation to maternal high-fat/high-sucrose (HF/HS) diet develop altered bile acid (BA) homeostasis. We hypothesized that these reflect an altered microbiome and asked if microbiota transplanted from HF/HS offspring change hepatic BA and lipid metabolism to determine the directionality of effect. Female mice were fed HF/HS or chow (CON) for 6 wk and bred with lean males. 16S sequencing was performed to compare taxa in offspring. Cecal microbiome transplantation (CMT) was performed from HF/HS or CON offspring into antibiotic-treated mice fed chow or high fructose. BA, lipid metabolic, and gene expression analyses were performed in recipient mice. Gut microbiomes from HF/HS offspring segregated from CON offspring, with increased Firmicutes to Bacteriodetes ratios and Verrucomicrobial abundance. After CMT was performed, HF/HS-recipient mice had larger BA pools, increased intrahepatic muricholic acid, and decreased deoxycholic acid species. HF/HS-recipient mice exhibited downregulated hepatic Mrp2, increased hepatic Oatp1b2, and decreased ileal Asbt mRNA expression. HF/HS-recipient mice exhibited decreased cecal butyrate and increased hepatic expression of Il6. HF/HS-recipient mice had larger livers and increased intrahepatic triglyceride versus CON-recipient mice after fructose feeding, with increased hepatic mRNA expression of lipogenic genes including Srebf1, Fabp1, Mogat1, and Mogat2. CMT from HF/HS offspring increased BA pool and shifted the composition of the intrahepatic BA pool. CMT from HF/HS donor offspring increased fructose-induced liver triglyceride accumulation. These findings support a causal role for vertical transfer of an altered microbiome in hepatic BA and lipid metabolism in HF/HS offspring.NEW & NOTEWORTHY We utilized a mouse model of maternal obesogenic diet exposure to evaluate the effect on offspring microbiome and bile acid homeostasis. We identified shifts in the offspring microbiome associated with changes in cecal bile acid levels. Transfer of the microbiome from maternal obesogenic diet-exposed offspring to microbiome-depleted mice altered bile acid homeostasis and increased fructose-induced hepatic steatosis.

Long-Term Follow-Up of Tufting Enteropathy Caused by EPCAM Mutation p.Asp253Asn and Absent EPCAM Expression.

Tufting enteropathy (TE) is caused by recessive epithelial cell adhesion molecule (EPCAM) mutations, features congenital intractable diarrhea, growth retardation, and a characteristic disorganization of surface enterocytes. TE generally requires parenteral nutrition (PN) throughout childhood and into adulthood or a small bowel transplantation. We report 2 siblings with TE; a 3-year-old patient 1 intermittently receives partial PN, monthly somatostatin therapy, tolerates a normal diet and has a normal stool output. However, she is the sixth patient of 90 TE patients in literature, to develop a chronic arthritis. A 12-year-old patient 2 is on a normal diet, and did not require PN for the past 8 years. Duodenal biopsies showed characteristic tufts, and a complete lack of EPCAM staining. Both siblings were homozygous for EPCAM mutation c.757G>A (p.Asp253Asn). This observation shows that an overall favorable outcome can be obtained in TE, even with abrogated intestinal EPCAM expression.

Left congenital diaphragmatic hernia-associated musculoskeletal deformities.

AIM: With the advancement in the treatment strategies of congenital diaphragmatic hernia (CDH), there is an increase in the survival rates. This fact leads to an increase in the morbidity and extrapulmonary complications in the long term such as failure to thrive, hernia recurrence, neurodevelopmental delay, gastrointestinal problems, and musculoskeletal anomalies. Herein, we aim to investigate the association between the long-term musculoskeletal complications in CDH patients regarding the defect size, repair type, and perinatal parameters. METHODS: After Institutional Review Board approval was obtained (2017-6361), a retrospective chart review was performed on CDH patients from 2003 to 2016. Patients who were operated due to left-sided isolated congenital diaphragmatic hernia and survived to date were included in the study. Data were collected on demographics, preoperative characteristics, operative interventions, and postoperative outcomes. Statistical analysis was performed with IBM SPSS Statistics 20.0.0 (Chicago, IL). RESULTS: There were 98 patients with left CDH of whom 33 (33.7%) had primary repair, 25 (25.5%) had patch repair, and 40 (40.8%) had muscle flap repair. The median age of the patients was 6.00 ± 3.83 years. 45 patients (45.9%) had large diaphragmatic defects, 28 patients (28.6%) had at least one type of musculoskeletal deformities, 2 of which were pectus carinatum, 16 were pectus excavatum, and 18 were scoliosis. CDH patients who had small diaphragmatic defects and repaired with a patch were less likely develop musculoskeletal deformities while who had primary abdominal closure after ventral hernia significantly have more pectus excavatum. CONCLUSION: Although there was a trend towards an increased risk of the pectus deformity and scoliosis in patients repaired with muscle flap, it did not reach statistical significance. There is a correlation between musculoskeletal deformities and the severity of the CDH.