Implications of Microbiota and Immune System in Development and Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent type of liver disease worldwide. The exact pathophysiology behind MASLD remains unclear; however, it is thought that a combination of factors or "hits" act as precipitants for disease onset and progression. Abundant evidence supports the roles of diet, genes, metabolic dysregulation, and the intestinal microbiome in influencing the accumulation of lipids in hepatocytes and subsequent progression to inflammation and fibrosis. Currently, there is no cure for MASLD, but lifestyle changes have been the prevailing cornerstones of management. Research is now focusing on the intestinal microbiome as a potential therapeutic target for MASLD, with the spotlight shifting to probiotics, antibiotics, and fecal microbiota transplantation. In this review, we provide an overview of how intestinal microbiota interact with the immune system to contribute to the pathogenesis of MASLD and metabolic dysfunction-associated steatohepatitis (MASH). We also summarize key microbial taxa implicated in the disease and discuss evidence supporting microbial-targeted therapies in its management.

COVID-19 vaccine acceptance and uptake among caregivers of children aged 5-11 years in Ontario, Canada: A cross-sectional survey.

INTRODUCTION: Although COVID-19 vaccine safety in 5-11-year-old children has been documented, half of Ontarian children this age remain unvaccinated. This study aimed to assess caregivers' vaccine acceptance for 5-11-year-old children and identify factors associated with vaccine non-acceptance. METHODS: A multi-language self-administered survey was sent to caregivers of 5-11-year-old children through schools and community health centers within the Greater Toronto Area from April-July 2022. Sociodemographic characteristics and immunization behaviours were collected for caregivers, their 5-11-year-old children, and any older siblings. The primary outcome, COVID-19 vaccine acceptance, was previous uptake of COVID-19 vaccine or caregiver intent to vaccinate for their 5-11-year-old child. Data were analyzed using descriptive statistics and multivariable logistic regression. RESULTS: In total, 807 caregivers were included in analysis. Although 93 % of caregivers had received two doses of COVID-19 vaccine, 77 % had a 5-11-year-old child who received at least one dose of vaccine. Caregivers age was associated with vaccine acceptance (vs. < 40 years; adjusted odds ratio [aOR] 2.1, 95 % confidence interval [CI] 1.4-3.1 for ages 40-49; aOR 2.8, 95 % CI 1.1-7.1 for ages ≥50 years). Immunization factors associated with vaccine acceptance included caregiver COVID-19 vaccination (aOR 38.1 vs. unvaccinated caregivers; 95 % CI 15.8-92.3), older siblings COVID-19 vaccination (aOR 49.2 vs. unvaccinated siblings; 95 % CI 18.3-132.3), and recent influenza vaccination for the child (aOR 6.9 vs. no influenza vaccine; 95 % CI 4.6-10.5). Among 189 caregivers with unvaccinated 5-11-year-old children, the most common reasons for non-acceptance were concerns about long-term side effects (59 %), lack of experience vaccinating children (41 %), and concerns that vaccines were developed too quickly (39 %). CONCLUSION: Acceptance of COVID-19 vaccination for 5-11-year-old children were associated with caregiver vaccine behaviors and sociodemographic factors. These findings highlight groups of caregivers that can be targeted for educational interventions and concerns that may be addressed to increase vaccine confidence.

Probiotics and non-alcoholic fatty liver disease in children and adolescents: a systematic review.

BACKGROUND: non-alcoholic fatty liver disease (NAFLD) in childhood is an increasing global public health issue with significant long-term consequences. NAFLD management mainly consists of lifestyle modifications, however, adjunct pharmacological therapies are currently lacking. Gut microbiota manipulation via probiotics may alter the course of pediatric NAFLD. The objective of this systematic review was to synthesize all the available literature on the use of probiotics in children and adolescents with NAFLD. METHODS: PubMed, EBSCOhost, Scopus, Web of Science, and Cochrane Library were systematically searched for trials on the use of probiotics in pediatric NAFLD. A quantitative DerSimonian Laird random effects meta-analysis was performed when possible; otherwise, a narrative summary of the study outcomes was presented and discussed. A separate search was completed to include all the ongoing registered trials on probiotics use in pediatric NAFLD. RESULTS: five randomized controlled trials met the inclusion criteria. Of these, four trials were included in the final quantitative analysis. Probiotic therapy significantly reduced the levels of alanine aminotransferase (ALT) (mean difference: -10.39 [-19.85, -0.93]), however significant heterogeneity between studies was identified (I2, 93 %). CONCLUSIONS: there is insufficient evidence to support probiotics in the treatment of pediatric NAFLD given the substantial degree of discordance amongst the available trials. Lifestyle modifications focusing on maintaining a normal BMI and regular exercise continue to be the gold standard approach to treating NAFLD in children.

Probiotics and non-alcoholic fatty liver disease in children and adolescents: a systematic review

Background: non-alcoholic fatty liver disease (NAFLD) in childhood is an increasing global public health issue with significant long-term consequences. NAFLD management mainly consists of lifestyle modifications, however, adjunct pharmacological therapies are currently lacking. Gut microbiota manipulation via probiotics may alter the course of pediatric NAFLD. The objective of this systematic review was to synthesize all the available literature on the use of probiotics in children and adolescents with NAFLD. Methods: PubMed, EBSCOhost, Scopus, Web of Science, and Cochrane Library were systematically searched for trials on the use of probiotics in pediatric NAFLD. A quantitative DerSimonian Laird random effects meta-analysis was performed when possible; otherwise, a narrative summary of the study outcomes was presented and discussed. A separate search was completed to include all the ongoing registered trials on probiotics use in pediatric NAFLD. Results: five randomized controlled trials met the inclusion criteria. Of these, four trials were included in the final quantitative analysis. Probiotic therapy significantly reduced the levels of alanine aminotransferase (ALT) (mean difference: -10.39 [-19.85, -0.93]), however significant heterogeneity between studies was identified (I2, 93 %). Conclusions: there is insufficient evidence to support probiotics in the treatment of pediatric NAFLD given the substantial degree of discordance amongst the available trials. Lifestyle modifications focusing on maintaining a normal BMI and regular exercise continue to be the gold standard approach to treating NAFLD in children (AU)

Alterations in the Rectal Sensitivity of Children With Chronic Constipation Evaluated by High-Resolution Anorectal Manometry.

Introduction Constipation is one of the most frequent chronic disorders in children and is almost always of functional etiology. Manometric alterations in anorectal sensitivity in children with chronic constipation are described in the literature; nevertheless, the impact of the duration of constipation on the parameters of anorectal manometry sensitivity is unknown. Objective To compare the parameters of sensitivity of high-resolution anorectal manometry (first sensation, threshold volume for urgency, and maximal tolerability) in children with chronic constipation, related to the time of evolution from the beginning of the symptoms. Methods This was a retrospective observational analytic study. The data of 39 children with functional constipation who were subjected to high-resolution anorectal manometry were included to evaluate constipation. The patients were divided into three groups according to the duration of constipation: <1 year; from 1 to 2 years; and >2 years. The parameters of sensitivity of the anorectal manometry were compared between the three groups and correlation tests were performed with the duration in months from the beginning of the symptoms of constipation. Results There was no difference between the sensitivity parameters of high-resolution anorectal manometry of the three groups; no correlation of these parameters with the time of evolution of the symptoms was found. Conclusions Alterations in the anorectal distensibility could develop early in the course of the disease, even from the first year of the beginning of the symptoms.

Differential Cytokine Expression in the Duodenum and Rectum of Children with Non-Immunoglobulin E-Mediated Cow's Milk Protein Allergy.

BACKGROUND: Cow's milk protein allergy (CMPA) is the most prevalent food allergy in children, and its pathogenesis remains poorly understood. It has been shown that the combination of genetic predisposition, perinatal factors, and intestinal imbalance of the immune response mediated by cytokines may play an essential role in CMPA pathogenesis. AIM: To characterize the gene expression of Th1, Th2, and Th17 cytokines in the duodenum and rectum in patients with CMPA. METHODS: This is an observational, descriptive, cross-sectional, prospective study. We used specific IgE (ImmunoCAP®) in serum and biopsies from the rectum and duodenum for the detection of cytokine messenger RNA levels by real-time PCR in patients with a positive oral food challenge for CMPA. We analyzed the relative quantification of the gene expression of cytokines by real-time PCR, and we used the housekeeping gene GAPDH for normalization purposes. RESULTS: Thirty children (13 male and 17 female) were evaluated. All patients had an open challenge for CMPA. IgE specific to casein, alfa-lactalbumin, and beta-lactoglobulin was negative in all patients. In terms of cytokine levels, the levels of TNFα, IL-6, IL-12 (Th1), IL-4, IL-10, IL-13 (Th2), and IL-17 were found to be higher in the rectum than in the duodenum (p < 0.05). IL-15 was found to be higher in the duodenum than in the rectum (p < 0.05). CONCLUSIONS: In the present study we observed that the immune response in CMPA seems to be mediated by a Th1, Th2, and Th17 cytokine profile, with the rectum being the main affected site.

Esophageal motility disorders in children with dysphagia: the utility of the Chicago classification

BACKGROUND: esophageal manometry is the standard criterion for the evaluation of dysphagia and the diagnosis of a primary motor disorder of the esophagus in adults and children. AIMS: to describe the diagnosis according to the Chicago classification (CC) v3.0 in children with dysphagia, in whom an esophageal motility disorder was documented. The associated comorbidities were also determined. METHODS: an observational retrospective study was performed of 54 patients evaluated for dysphagia, who had undergone a high-resolution manometry (HREM). RESULTS: a normal HREM was found in 52 % (n = 28) of the children, whereas 48 % (n = 26) had some esophageal motility disorder. The most frequent diagnosis was ineffective esophageal motility and achalasia. Excluding previously healthy children, most children had a history of autoimmune disease and intellectual disability. CONCLUSIONS: an esophageal motor disorder can be diagnosed in nearly half of infants and children with dysphagia. In this study, all esophageal diseases could be classified according to the CC v3.0. HREM should be considered for the evaluation of children with dysphagia, in addition to other studies

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Esophageal motility disorders in children with dysphagia: the utility of the Chicago classification.

BACKGROUND: esophageal manometry is the standard criterion for the evaluation of dysphagia and the diagnosis of a primary motor disorder of the esophagus in adults and children. AIMS: to describe the diagnosis according to the Chicago classification (CC) v3.0 in children with dysphagia, in whom an esophageal motility disorder was documented. The associated comorbidities were also determined. METHODS: an observational retrospective study was performed of 54 patients evaluated for dysphagia, who had undergone a high-resolution manometry (HREM). RESULTS: a normal HREM was found in 52 % (n = 28) of the children, whereas 48 % (n = 26) had some esophageal motility disorder. The most frequent diagnosis was ineffective esophageal motility and achalasia. Excluding previously healthy children, most children had a history of autoimmune disease and intellectual disability. CONCLUSIONS: an esophageal motor disorder can be diagnosed in nearly half of infants and children with dysphagia. In this study, all esophageal diseases could be classified according to the CC v3.0. HREM should be considered for the evaluation of children with dysphagia, in addition to other studies.

The effects of tocotrienol supplementation on lipid profile: A meta-analysis of randomized controlled trials.

BACKGROUND & OBJECTIVE: Tocotrienol supplementation has been emerged as a potent candidate for the treatment of dyslipidemia. In the present study, a systematic review and meta-analysis of randomized controlled trials was performed with the aim of examining the effects of tocotrienol supplementation on the lipid profile. METHODS: Four databases (Scopus, PubMed/Medline, Web of Science and Embase) were used to accomplish the literature search up to November 2019. Clinical trials encompassing the impact of tocotrienol supplementation on lipid profile were extracted regardless of clinical condition, with studies included involving only adults patients. RESULTS: A total of 15 articles with 20 arms were eligible and included in the meta-analysis to estimate the pooled effect size. Overall results showed a significant effect of tocotrienol supplementation on increasing high-density lipoprotein cholesterol (HDL-C) levels (weight mean difference (WMD): 0.146 mmol/L, I2 = 85.9%) and a non-significant influence on total cholesterol (TC) (WMD: 0.010 mmol/L, I2 = 64.5%), low-density lipoprotein cholesterol (LDL-C) (WMD: 0.095 mmol/L, I2 = 87.4%), and triglycerides (TG) (WMD: -0.112 mmol/L, I2 = 67.4%) levels. Increment in HDL-C levels was significant greater for the tocotrienol dosage ≥ 200 mg/d (WMD: 0.202 mmol/L) and ≤8 weeks (WMD: 0.278 mmol/L). Moreover, studies that investigated tocotrienol dose ≥200 mg had no heterogeneity, while showing a significant decrease in TG levels (WMD: -0.177 mmol/L). CONCLUSION: The present meta-analysis demonstrated that supplementing with tocotrienols does not decrease the concentrations of LDL-C, TC and TG. However, tocotrienol supplementation was considered a candidate for increasing HDL-C levels.

Functional Constipation and the Gut Microbiome in Children: Preclinical and Clinical Evidence.

Functional constipation is a common condition in childhood with significant impact on patients' quality of life and on health care resources. Functional constipation is characterized by decreased bowel movements and/or hard stools, which cause significant distress for children and their caregivers. While the term "functional" may imply the absence of organic causes with a focus on behavioral aspects, 40% of children continue to have symptoms beyond conventional management with one in four children continuing to experience constipation into adulthood. The refractory and chronic nature of constipation highlights the importance of considering a range of pathophysiological mechanisms, including the potential role of the gut microbiome. In this review, we provide an overview of preclinical and clinical studies that focus on the potential mechanisms through which the gut microbiome might contribute to the clinical presentation of functional constipation in pediatrics.

Small intestinal bacterial overgrowth: could it be associated with chronic abdominal pain in children with allergic diseases?

Background and aims: small intestinal bacterial overgrowth (SIBO) is a well-known cause of chronic abdominal pain (CAP) during the pediatric age. On the other hand, children with a history of some allergic disorder present CAP more frequently. The aim of this study was to determine the association between the presence of allergic diseases and SIBO in patients diagnosed with CAP. Materials and methods: this was an observational, analytical, retrospective study. Children with CAP who had undergone a lactulose hydrogen breath test to determine the presence of SIBO were included in the study. All patients underwent an evaluation for allergies by means of a skin prick test or the determination of specific IgE, according to clinical diagnosis. The study groups were established according to the presence of SIBO and the results of the allergic evaluation were statistically compared between the groups. Results: seventy patients were included (41 females and 29 males) and SIBO was diagnosed in 35 patients. In addition, 71.4% of children with SIBO were found to have an allergic disease, in contrast with 28.6% of children without SIBO (p = 0.001). The odds ratio for having any type of allergy in patients with SIBO was 5.45 (95% CI, 1.96-15.17; p = 0.001). Conclusions: we found an association between SIBO and allergic disease, especially allergic rhinitis, cow's milk protein allergy and asthma. Thus, SIBO should be ruled out in pediatric patients with CAP and allergic disease

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Small intestinal bacterial overgrowth: could it be associated with chronic abdominal pain in children with allergic diseases?

BACKGROUND AND AIMS: small intestinal bacterial overgrowth (SIBO) is a well-known cause of chronic abdominal pain (CAP) during the pediatric age. On the other hand, children with a history of some allergic disorder present CAP more frequently. The aim of this study was to determine the association between the presence of allergic diseases and SIBO in patients diagnosed with CAP. MATERIALS AND METHODS: this was an observational, analytical, retrospective study. Children with CAP who had undergone a lactulose hydrogen breath test to determine the presence of SIBO were included in the study. All patients underwent an evaluation for allergies by means of a skin prick test or the determination of specific IgE, according to clinical diagnosis. The study groups were established according to the presence of SIBO and the results of the allergic evaluation were statistically compared between the groups. RESULTS: seventy patients were included (41 females and 29 males) and SIBO was diagnosed in 35 patients. In addition, 71.4% of children with SIBO were found to have an allergic disease, in contrast with 28.6% of children without SIBO (p = 0.001). The odds ratio for having any type of allergy in patients with SIBO was 5.45 (95% CI, 1.96-15.17; p = 0.001). CONCLUSIONS: we found an association between SIBO and allergic disease, especially allergic rhinitis, cow's milk protein allergy and asthma. Thus, SIBO should be ruled out in pediatric patients with CAP and allergic disease.

Small Intestinal Bacterial Overgrowth in Children: A State-Of-The-Art Review.

Small intestinal bacterial overgrowth (SIBO) is a heterogenous and poorly understood entity characterised by an excessive growth of select microorganisms within the small intestine. This excessive bacterial biomass, in turn, disrupts host physiology in a myriad of ways, leading to gastrointestinal and non-gastrointestinal symptoms and complications. SIBO is a common cause of non-specific gastrointestinal symptoms in children, such as chronic abdominal pain, abdominal distention, diarrhoea, and flatulence, amongst others. In addition, it has recently been implicated in the pathophysiology of stunting, a disease that affects millions of children worldwide. Risk factors such as acid-suppressive therapies, alterations in gastrointestinal motility and anatomy, as well as impoverished conditions, have been shown to predispose children to SIBO. SIBO can be diagnosed via culture-dependant or culture-independent approaches. SIBO's epidemiology is limited due to the lack of uniformity and consensus of its diagnostic criteria, as well as the paucity of literature available. Antibiotics remain the first-line treatment option for SIBO, although emerging modalities such as probiotics and diet manipulation could also have a role. Herein, we present a state-of-the-art-review which aims to comprehensively outline the most current information on SIBO in children, with particular emphasis on the gut microbiota.

Childhood obesity in Mexico: social determinants of health and other risk factors.

Approximately 50 million children and adolescents in Latin America are affected by the childhood obesity pandemic. We present the case of a 5-year-old Mexican girl with obesity and gastro-oesophageal reflux disease (GORD), in whom prenatal, lifestyle and environmental risk factors were identified. Here, we demonstrate how childhood obesity is rooted since pregnancy and the perinatal stage, and how the social determinants of health like unsafe outdoor conditions, lack of infrastructure to exercise and a suboptimal physical activity curriculum in government schools strongly influence the development and maintenance of childhood obesity and complicate management.

A tip from the nose: rhinocerebral mucormycosis in a patient with alcoholic liver cirrhosis and cocaine abuse, an uncommon association.

We present the case of a 28-year-old man with a long-standing history of cocaine abuse and Child-Pugh class C alcoholic liver cirrhosis who developed severe lower respiratory tract infection complicated with septic shock and multiple organ dysfunction. He was managed in the intensive care unit. On the eighth day after admission, he developed a nose discolouration, which was initially thought to be associated with high-dose vasopressors. Despite the reduction of vasopressors, the lesion progressed rapidly. It was later diagnosed as rhinocerebral mucormycosis. Amphotericin B was administered, but unfortunately the patient succumbed to the complications postinfection. The association between alcoholic liver cirrhosis and rhinocerebral mucormycosis should be known and prompt recognition warrants immediate treatment.