Alcohol, the gut microbiome, and liver disease.

The microorganisms inhabiting our gastrointestinal tract are critical for human health. Chronic heavy alcohol use can modulate the composition and function of the gut microbiota, thereby exacerbating end-organ damage via the gut-brain axis and the gut-liver axis. In this review, we summarize the bacterial, fungal, and viral gut microbial compositional changes associated with alcohol use and alcohol-associated liver disease and discuss the mechanisms of action by which gut dysbiosis reinforces alcohol use behavior and liver inflammation and injury. We also highlight important pre-clinical and clinical trials that target gut microbial-specific mechanisms for the treatment of alcohol use disorder and alcohol-associated liver disease.

How Many Patients Who Have a Clubfoot Treated Using the Ponseti Method are Likely to Undergo a Tendon Transfer?

BACKGROUND: The Ponseti method has become the standard of care for the treatment of idiopathic clubfoot. A commonly reported problem encountered with this technique is a relapsed deformity that is sometimes treated in patients older than 2.5 years by an anterior tibial tendon transfer (ATTT) to the third cuneiform. Presently, there is insufficient information to properly counsel families whose infants are beginning Ponseti treatment on the probability of needing later tendon transfer surgery. METHODS: All idiopathic clubfoot patients seen at the authors' institution during the study period who met the inclusion criteria and who were followed for >2.5 years were included (N=137 patients). Kaplan-Meier Survival analysis was used to determine the probability of survival without the need for ATTT surgery. In addition, the influence of patient characteristics, socioeconomic variables, and treatment variables on need for surgery was calculated. RESULTS: On the basis of the survivorship analysis, the probability of undergoing an ATTT remained below 5% for all patients at 3 years of age, but exceeded 15% by 4 years of age, increasing steadily afterwards such that by 6 years of age, the probability of undergoing an ATTT reached 29% of all patients. Overall, controlling for all other variables in the analysis, parent-reported adherence with bracing reduced the odds of undergoing surgery by 6.88 times, compared with parent-reported nonadherence (P<0.01). CONCLUSIONS: This is the first study to report the probability of undergoing ATTT surgery as a function of age using survivorship analysis following Ponseti clubfoot treatment. Although the overall probability reached 29% at 6 years, this was significantly reduced by compliance with bracing. This information may be useful to the clinician when counseling families at the start of treatment. LEVEL OF EVIDENCE: Level III-theraputic.

The Influence of Sex and Laterality on Clubfoot Severity.

BACKGROUND: Idiopathic clubfoot is bilateral in approximately 50% of cases and has been widely reported to affect males more frequently than females. Despite these observations, the correlation between sex and severity of the deformity has not been established. As well, the difference in severity between unilateral and bilateral clubfeet has not been extensively investigated. Therefore, the goals of the present study were to: (1) examine the relationship between sex and severity of deformity and (2) determine the relationship between laterality and severity of deformity. METHODS: The families of infants with idiopathic clubfoot deformity treated at our institution were prospectively invited to participate in this institutional review board-approved study. Severity of the deformity was assessed by a single surgeon for each patient using the Dimeglio criteria at the first clinic visit. After evaluating the distributions, the correlations were quantified by nonparametric analyses. RESULTS: Over 8 years, 240 infants met the inclusion criteria. There was no significant difference in the severity of deformity due to sex (P=0.61): the median Dimeglio score for males was 13 (variance 4.8) and for females, the median was 13.0 (variance of 5.1). In contrast, severity was distributed differently among unilateral versus bilateral patients. Although both unilateral and bilateral patients had a median Dimeglio score of 13, the ratio of bilateral patients was higher among those with moderate or very severe deformities compared with those with severe deformities (P<0.01). CONCLUSIONS: Although idiopathic clubfoot is commonly considered to affect male patients disproportionately, this is the first study to document no difference in severity due to sex. Further, this study demonstrated that on average, bilateral patients did not have increased severity, but presented with a larger range of severity than those patients with unilateral deformity. LEVEL OF EVIDENCE: Level III-prognostic.

Metabolomic Predictors of Non-alcoholic Steatohepatitis and Advanced Fibrosis in Children.

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in western countries both in children and adults. Metabolic dysregulation associated with gut microbial dysbiosis may influence disease progression from hepatic steatosis to inflammation and subsequent fibrosis. Using a multi-omics approach, we profiled the oral and fecal microbiome and plasma metabolites from 241 predominantly Latino children with non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver (NAFL), and controls. Children with more severe liver pathology were dysbiotic and had increased gene content associated with lipopolysaccharide biosynthesis and lipid, amino acid and carbohydrate metabolism. These changes were driven by increases in Bacteroides and concomitant decreases of Akkermansia, Anaerococcus, Corynebacterium, and Finegoldia. Non-targeted mass spectrometry revealed perturbations in one-carbon metabolism, mitochondrial dysfunction, and increased oxidative stress in children with steatohepatitis and fibrosis. Random forests modeling of plasma metabolites was highly predictive of non-alcoholic steatohepatitis (NASH) (97% accuracy) and hepatic fibrosis, steatosis and lobular inflammation (93.8% accuracy), and can differentiate steatohepatitis from simple steatosis (90.0% accuracy). Multi-omics predictive models for disease and histology findings revealed perturbations in one-carbon metabolism, mitochondrial dysfunction, and increased oxidative stress in children with steatohepatitis and fibrosis. These results highlight the promise of non-invasive biomarkers for the growing epidemic of fatty liver disease.