L. Pierri

Multiple gut–liver axis abnormalities in children with obesity with and without hepatic involvement

Gut–liver axis (GLA) dysfunction appears to play a role in obesity and obesity‐related hepatic complications.

Gut–Liver Axis Derangement in Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is the most frequent type of chronic liver disease in the pediatric age group, paralleling an obesity pandemic. A “multiple-hit” hypothesis has been invoked to explain its pathogenesis. The “first hit” is liver lipid accumulation in obese children with insulin resistance. In the absence of significant lifestyle modifications leading to weight loss and increased physical activity, other factors may act as “second hits” implicated in liver damage progression leading to more severe forms of inflammation and hepatic fibrosis. In this regard, the gut–liver axis (GLA) seems to play a central role. Principal players are the gut microbiota, its bacterial products, and the intestinal barrier. A derangement of GLA (namely, dysbiosis and altered intestinal permeability) may promote bacteria/bacterial product translocation into portal circulation, activation of inflammation via toll-like receptors signaling in hepatocytes, and progression from simple steatosis to non-alcoholic steato-hepatitis (NASH). Among other factors a relevant role has been attributed to the farnesoid X receptor, a nuclear transcriptional factor activated from bile acids chemically modified by gut microbiota (GM) enzymes. The individuation and elucidation of GLA derangement in NAFLD pathomechanisms is of interest at all ages and especially in pediatrics to identify new therapeutic approaches in patients recalcitrant to lifestyle changes. Specific targeting of gut microbiota via pre-/probiotic supplementation, feces transplantation, and farnesoid X receptor modulation appear promising.

Urinary Metabolomics in Pediatric Obesity and NAFLD Identifies Metabolic Pathways/Metabolites Related to Dietary Habits and Gut-Liver Axis Perturbations

To get insight into still elusive pathomechanisms of pediatric obesity and non-alcoholic fatty liver disease (NAFLD) we explored the interplay among GC-MS studied urinary metabolomic signature, gut liver axis (GLA) abnormalities, and food preferences (Kid-Med). Intestinal permeability (IP), small intestinal bacterial overgrowth (SIBO), and homeostatic model assessment-insulin resistance were investigated in forty children (mean age 9.8 years) categorized as normal weight (NW) or obese (body mass index <85th or >95th percentile, respectively) ± ultrasonographic bright liver and hypertransaminasemia (NAFLD). SIBO was increased in all obese children (p = 0.0022), IP preferentially in those with NAFLD (p = 0.0002). The partial least-square discriminant analysis of urinary metabolome correctly allocated children based on their obesity, NAFLD, visceral fat, pathological IP and SIBO. Compared to NW, obese children had (1) higher levels of glucose/1-methylhistidine, the latter more markedly in NAFLD patients; and (2) lower levels of xylitol, phenyl acetic acid and hydroquinone, the latter especially in children without NAFLD. The metabolic pathways of BCAA and/or their metabolites correlated with excess of visceral fat centimeters (leucine/oxo-valerate), and more deranged IP and SIBO (valine metabolites). Urinary metabolome analysis contributes to define a metabolic fingerprint of pediatric obesity and related NAFLD, by identifying metabolic pathways/metabolites reflecting typical obesity dietary habits and GLA perturbations.

Emerging pathomechanisms involved in obesity.

Objective: Overweight/obesity prevalence has increased dramatically worldwide. Recent evidence suggests sleep deprivation/fragmentation, fructose-exceedingly rich diets, and exposure to endocrine disruptors (eg, bisphenol A, BPA) as emerging additional factors involved in pathomechanisms and in the treatment resistance of obesity and its complications. Our study focuses on these factors for further preventive/therapeutic approaches in paediatric obesity. Methods: Fifty-four Italian children (cases: n = 31 overweight/obese; controls: n = 23 normal weight) were clinically/anthropometrically characterised. Parents completed questionnaires on the relation between obesogenic factors and childhood obesity. BPA was measured by gas chromatography/tandem mass spectrometry on early morning urine samples. Correlations between the continuous variables were analysed using Spearman rank correlation. Results: Sleep deprivation/fragmentation, nocturnal breathing problems, and daytime sleepiness increased with increasing body mass index, correlating with the presence of clinical markers of metabolic syndrome (eg, acanthosis nigricans). Frequency of sugar-enriched drink consumption and the amount of fructose per portion and/or per week increased, paralleling the ponderal excess and all the other anthropometric parameters. In the entire sample population, free and total BPA levels increased paralleling the body mass index increase (r > 0.8), whereas the conjugate demonstrated the opposite trend. The re-use of disposable plastic showed a positive correlation with urinary BPA levels. Conclusions: Despite its exploratory nature, the results of our pilot study confirm the close relation between certain factors and paediatric obesity, underscoring their role as emerging targets for prevention and therapy.

Probiotics to Treat Visceral Obesity and Related Liver Disease

Obesity and its related complications have reached epidemic proportions that cannot be completely explained by energy imbalance between dietary calories and physical exercise. Increasing interest is therefore developing in a number of recently identified obesogenic triggering factors (e.g. endocrine disruptors, sleep deprivation, fructose intake, gut-liver axis, and intestinal microbiota). In this chapter, we will focus on recent advances in our knowledge of the gut-liver axis and gut microbiota, which suggest that: (1) age, geographical origin, breastfeeding, diet, and lifestyle may all influence microbiome composition;

Relations of gut liver axis components and gut microbiota in obese children with fatty liver: A pilot study

The prevalence of metabolic syndrome and its hepatic component — non-alcoholic fatty liver disease (NAFLD) — has increased alarmingly, paralleling the worldwide obesity epidemics. The pathophysiology of NAFLD is not clearly understood, but it has been proposed to be the result of multiple ‘‘hits’’[1]. A number of studies increasingly supports the pathogenetic role also of the gut microbiota (GM) both in NAFLD onset and progression. In this respect, GM would exert its noxious effects through the dysfunction of the gut-liver axis (GLA), which includes some or all of the following components: increased intestinal permeability (IP), endogenous ethanol (ETOH) and systemic endotoxin (LPS) concentrations [2,3]. As these players have hitherto not been simultaneously investigated in the same patient [reviewed in reference 4], the aim of our study was to explore the possible existence of reciprocal influences of several GLA components and GM composition in the same group of well characterized obese (Ob) children with and without fatty liver compared to normal-weight (NW) control peers. We studied 10 Ob Italian children, consecutively recruited at our center after parental agreement and written informed consent. The inclusion criteria were age 8—13 years, and a body mass index (BMI) > 97th percentile. Six non-Ob and non-overweight (BMI < 85th percentile), healthy normal-weight (NW) controls with normal anthropometric, clinical, laboratory and ultrasonographic (US) hepatic parameters and no other associated diseases were recruited among patients of the Pediatric Surgery Section listed for elective minor surgery. Lifestyle including eventual medications or alcohol exposition and total daily fructose and caloric intake and food preferences were investigated by multiple-choice questionnaires [5]. Weight, height, BMI values and percentiles,