The regeneration of the mucosal interface of the human intestine is critical in the host–gut microbiome crosstalk associated with gastrointestinal diseases. The biopsy-derived intestinal organoids provide genetic information of patients with physiological cytodifferentiation. However, the enclosed lumen and static culture condition substantially limit the utility of patient-derived organoids for microbiome-associated disease modeling. Here, we report a patient-specific three-dimensional (3D) physiodynamic mucosal interface-on-a-chip (PMI Chip) that provides a microphysiological intestinal milieu under defined biomechanics. The real-time imaging and computational simulation of the PMI Chip verified the recapitulation of non-linear luminal and microvascular flow that simulates the hydrodynamics in a living human gut. The multiaxial deformations in a convoluted microchannel not only induced dynamic cell strains but also enhanced particle mixing in the lumen microchannel. Under this physiodynamic condition, an organoid-derived epithelium obtained from the patients diagnosed with Crohn’s disease, ulcerative colitis, or colorectal cancer independently formed 3D epithelial layers with disease-specific differentiations. Moreover, co-culture with the human fecal microbiome in an anoxic–oxic interface resulted in the formation of stochastic microcolonies without a loss of epithelial barrier function. We envision that the patient-specific PMI Chip that conveys genetic, epigenetic, and environmental factors of individual patients will potentially demonstrate the pathophysiological dynamics and complex host–microbiome crosstalk to target a patient-specific disease modeling.

Controlled attenuation parameter (CAP) is a recently introduced, non-invasive and quantitative method to evaluate hepatic steatosis demonstrated in adults, but limited in obesity and not well evaluated in children. The aim of this study was to investigate the diagnostic performance for assessing hepatic steatosis grades using CAP in children based on MR proton density fat fraction (PDFF). Children evaluated for non-alcoholic fatty liver disease (NAFLD) who were assessed for PDFF and CAP were enrolled retrospectively. Hepatic steatosis grades 0–3 were classified according to PDFF using cutoff values of 6, 17.5, and 23.3%. Subgroup analyses were performed in non-obese and obese groups using the 95th percentile body mass index (BMI) as a cutoff and BMI30 group when BMI > 30 kg/m2. Pearson’s correlations between variables were also analyzed. In a total of 86 children, there were 53 in the obese group including 17 of the BMI30 group. CAP demonstrated 98.7% sensitivity and 80% specificity for diagnosing grades 1–3 vs. grade 0 using a cutoff value of 241 dB/m (area under the curve = 0.941, p < 0.001). The diagnostic performance for higher steatosis grades was suboptimal. CAP correlated with abdominal wall thickness in both obese (r = 0.549, p = 0.001) and non-obese (r = 0.386, p = 0.004) groups and did not correlate with PDFF in BMI30 group. In children with NAFLD, CAP showed excellent diagnostic performance for differentiating presence and absence of hepatic steatosis using a cutoff value of 241 dB/m. However, CAP was limited in evaluating grades of steatosis, especially in children with BMI > 30 kg/m2.

Non-alcoholic fatty liver disease (NAFLD) is complicated disease and increasing worldwide. Previously, many studies of NALFD prevalences have used alanine aminotransferase (ALT) of > 40 U/L to define NAFLD, although that is too high to be reliable among adolescents. This study aimed to define the upper normal limit of ALT among Korean adolescents, and use it to estimate the prevalence of NAFLD, based on data from the Korea National Health and Nutrition Examination Survey (KNHANES). Data were obtained from 1785 healthy adolescents (916 boys and 869 girls, 10–18 years old) who participated in the KNHANES during 2010–2015. The International Diabetes Federation metabolic syndrome criteria for adolescents were used to exclude participants with metabolic syndrome components. Furthermore, participants who previously had diseases related to low HDL levels, high TG levels, diabetes, or very low/high body mass index and hepatitis B were excluded. The 95th percentiles level of ALT from healthy participants were evaluated. The definition of NAFLD was overweight status (≥85th percentile of body mass index) plus elevated ALT levels (95th percentile). The upper normal ALT were 24.1 U/L for boys and 17.7 U/L for girls. Based on these values, the estimated prevalences of NAFLD in 2015 were 8.9% among adolescents. Defining the upper normal limit of ALT can be adjusted for each sex and ethnics in the general population. ALT laboratory thresholds used for children should be re-examined. The physicians should be aware not to underdiagnose NAFLD patient even ALT level is < 40 U/L.

Biliary atresia (BA) results in severe bile blockage and is caused by the absence of extrahepatic ducts. Even after successful hepatic portoenterostomy, a considerable number of patients are likely to show progressive deterioration in liver function. Recent studies show that mutations in protein-coding mitochondrial DNA (mtDNA) genes and/or mitochondrial genes in nuclear DNA (nDNA) are associated with hepatocellular dysfunction. This observation led us to investigate whether hepatic dysfunctions in BA is genetically associated with mtDNA mutations. We sequenced the mtDNA protein-coding genes in 14 liver specimens from 14 patients with BA and 5 liver specimens from 5 patients with choledochal cyst using next-generation sequencing. We found 34 common non-synonymous variations in mtDNA protein-coding genes in all patients examined. A systematic 3D structural analysis revealed the presence of several single nucleotide polymorphism-like mutations in critical regions of complexes I to V, that are involved in subunit assembly, proton-pumping activity, and/or supercomplex formation. The parameters of chronic hepatic injury and liver dysfunction in BA patients were also significantly correlated with the extent of hepatic failure, suggesting that the mtDNA mutations may aggravate hepatopathy. Therefore, mitochondrial mutations may underlie the pathological mechanisms associated with BA.

Kang Y, et al. J Korean Med Sci. 2018 Mar;33(14):e109. https://doi.org/10.3346/jkms.2018.33.e109