Intestinal Regulatory T Cells as Specialized Tissue-Restricted Immune Cells in Intestinal Immune Homeostasis and Disease

FOXP3+ regulatory T cells (Treg cells) are a specialized population of CD4+ T cells that restrict immune activation and are essential to prevent systemic autoimmunity. In the intestine, the major function of Treg cells is to regulate inflammation as shown by a wide array of mechanistic studies in mice. While Treg cells originating from the thymus can home to the intestine, the majority of Treg cells residing in the intestine are induced from FOXP3neg conventional CD4+ T cells to elicit tolerogenic responses to microbiota and food antigens. This process largely takes place in the gut draining lymph nodes via interaction with antigen-presenting cells that convert circulating naïve T cells into Treg cells. Notably, dysregulation of Treg cells leads to a number of chronic inflammatory disorders, including inflammatory bowel disease. Thus, understanding intestinal Treg cell biology in settings of inflammation and homeostasis has the potential to improve therapeutic options for patients with inflammatory bowel disease. Here, the induction, maintenance, trafficking, and function of intestinal Treg cells is reviewed in the context of intestinal inflammation and inflammatory bowel disease. In this review we propose intestinal Treg cells do not compose fixed Treg cell subsets, but rather (like T helper cells), are plastic and can adopt different programs depending on microenvironmental cues

Diagnostic testing in children: A qualitative study of pediatricians' considerations

Aims and Objectives: Studies in adult medicine have shown that physicians base testing decisions on the patient's clinical condition but also consider other factors, including local practice or patient expectations. In pediatrics, physicians and parents jointly decide on behalf of a (young) child. This might demand more explicit and more complex deliberations, with sometimes conflicting interests. We explored pediatricians' considerations in diagnostic test ordering and the factors that influence their deliberation. Method: We performed in-depth, semistructured interviews with a purposively selected heterogeneous sample of 20 Dutch pediatricians. We analyzed transcribed interviews inductively using a constant comparative approach, and clustered data across interviews to derive common themes. Results: Pediatricians perceived test-related burden in children higher compared with adults, and reported that avoiding an unjustified burden causes them to be more restrictive and deliberate in test ordering. They felt conflicted when parents desired testing or when guidelines recommended diagnostic tests pediatricians perceived as unnecessary. When parents demanded testing, they would explore parental concern, educate parents about harms and alternative explanations of symptoms, and advocate watchful waiting. Yet they reported sometimes performing tests to appease parents or to comply with guidelines, because of feared personal consequences in the case of adverse outcomes. Conclusion: We obtained an overview of the considerations that are weighed in pediatric test decisions. The comparatively strong focus on prevention of harm motivates pediatricians to critically appraise the added value of testing and drivers of low-value testing. Pediatricians' relatively restrictive approach to testing could provide an example for other disciplines. Improved guidelines and physician and patient education could help to withstand the perceived pressure to test

High predictability of impaired glucose tolerance by combining cardiometabolic screening parameters in obese children

There is debate on which overweight and obese children should be screened for the presence of impaired glucose tolerance (IGT) by oral glucose tolerance testing (OGTT). The objective of the study was to identify risk factors predictive of the presence of IGT. In a cohort of overweight children, who underwent OGTT, we determined the association of anthropometric and laboratory parameters with IGT and whether combining parameters improved the sensitivity of screening for IGT. Out of 145 patients, IGT was present in 11, of whom two had impaired fasting glucose (IFG). Elevated blood pressure (p=0.025) and elevated liver enzymes (p=0.003) were associated with IGT, whereas IFG was not (p=0.067), screening patients with either one of these parameters predicted IGT with a high sensitivity of 1.00, and a number needed to screen of 5.7. Screening all patients with either IFG, presence of elevated blood pressure and elevated liver enzymes, significantly increases predictability of IGT compared to using IFG alone

Cognitive function during 3 years of growth hormone in previously growth hormone-treated young adults with Prader-Willi syndrome

CONTEXT: Most patients with Prader-Willi syndrome (PWS) have mild to moderate cognitive impairment. Growth hormone (GH) treatment has positive short- and long-term effects on cognition in children with PWS. Few studies, however, have investigated the effects of GH on cognitive functioning in adults with PWS. OBJECTIVE: To investigate the effects of 3 years of GH treatment on cognitive functioning and behavior in young adults with PWS who were treated with GH during childhood. DESIGN: Open-label, prospective study. SETTING: Dutch PWS Reference Center. METHODS: Patients were treated with 0.33 mg GH/m²/day (∼0.012 mg/kg/day; 33% of childhood dose). Cognitive functioning was measured by Wechsler Adult Intelligence (WAIS) tests. Behavior was studied by a developmental behavior checklist-parents/caregivers (DBC-P). RESULTS: Forty-six young adults with PWS with a median age of 19 (IQR 17-21) years were investigated. Estimated mean (95% CI) total, verbal, and performance IQ remained stable during 3 years of GH-treatment. Total IQ being 66 (63-69) at the start and 67 (64-71) after 3 years (P = .30); Verbal IQ being 65 (62-68) and 66 (62-70), respectively (P = .31) and performance IQ being 67 (63-70) and 67 (63-72) resp. (P = .42). Estimated mean Total DBC score did not significantly change during 3 years of GH-treatment, being 36.3 at start and 36.5 after 3 years (P = .94) (P50). CONCLUSIONS: Three years of GH-treatment in young adults with PWS with 33% of the pediatric dose, maintains total, verbal, and performance IQ. The emotional and behavioral disturbances remained stable and were similar compared to peers with other intellectual disabilities.</p

Gut microbiota and its diet-related activity in children with intestinal failure receiving long-term parenteral nutrition

Background: This study characterized gut microbiota and its diet-related activity in children with intestinal failure (IF) receiving parenteral nutrition (PN) compared with those of healthy controls (HC) and in relation to disease characteristics. Methods: The fecal microbiota and short-chain fatty acids (SCFAs) were measured in 15 IF patients (n = 68) and 25 HC (n = 25). Results: Patients with IF had a lower bacterial load (P =.003), diversity (P <.001), evenness (P <.001) and richness (P = 0.006) than HC. Patients with surgical IF had lower diversity (P <.039) than those with functional IF. Propionic acid and butyric acid (p <.001) were lower and d-lactate and l-lactate were higher (p < 0.001) in IF patients than in HC. The energy supplied by PN (%PN) was negatively associated with microbiota diversity and SCFA profile. IF patients had more Escherichia-Shigella (P =.006), Cronobacter (P =.001), and Staphylococcus (Operational Taxonomic Unit 14, P <.001) and less Faecalibacterium (P < 0.001) and Ruminococcus 1 and 2 (P <.001). Duration of PN (P =.005), %PN (P =.005), and fiber intake (P =.011) were predictive of microbiota structure. Higher intake of enteral nutrition was associated with microbiota structure and function closer to those of HC. Conclusions: Microbiota composition and its diet-related function are altered in IF, with depletion of beneficial SCFAs and species and supraphysiological increase of potentially harmful pathobionts. The influence of this compositional and functional microbial dysbiosis on patients’ outcomes and management warrants further exploration

Gut microbiota and its diet-related activity in children with intestinal failure on long-term parenteral nutrition

Background: This study characterized the gut microbiota and its diet‐related metabolic activity in children with intestinal failure (IF) on parenteral nutrition (PN) compared with healthy controls and in relation to disease characteristics. Methods: Serial fecal samples were collected from 15 IF patients (n = 68) and from 25 healthy children (n = 25). The fecal microbiota, and short chain fatty acids (SCFA) were measured. Results: The microbiota of patients with IF had a lower bacterial load (p = 0.003), Shannon diversity index (p&lt;0.001), taxon evenness (p&lt;0.001) and richness (p = 0.006) than healthy controls. Patients with surgical IF had lower α‐diversity (p&lt;0.039) than those with functional IF. Patients with IF had less propionic and butyric acid (p&lt;0.001), and more D and L‐lactate than healthy controls (p&lt;0.001). The percentage of calories supplied by PN (%PN) was negatively associated with microbiota diversity and influenced SCFA profile. IF patients had more Escherichia‐Shigella (p = 0.006), Cronobacter (p = 0.001) and Staphylococcus (OTU 14, p&lt;0.001) and less Faecalibacterium (p&lt;0.001) and Ruminococcus 1 and 2 (p&lt;0.001). Duration of PN (R2 = 6%, p = 0.005), % of calories from PN (R2 = 6%, p = 0.005) and fiber intake (R2 = 5%, p = 0.011) were predictive of microbiota community structure. A higher intake of enteral nutrition was associated with a microbiota composition and function closer to that of the healthy status. Conclusions: The microbiota composition and its diet‐related function are altered in pediatric IF, with profound depletion of beneficial SCFA and species, and supraphysiological increase of potentially harmful pathobionts. The influence of this compositional and functional microbial dysbiosis on patients’ clinical outcomes and management warrants further exploration

Gut microbiota and its diet‐related activity in children with intestinal failure on long‐term parenteral nutrition

Background: This study characterized the gut microbiota and its diet‐related metabolic activity in children with intestinal failure (IF) on parenteral nutrition (PN) compared with healthy controls and in relation to disease characteristics. Methods: Serial fecal samples were collected from 15 IF patients (n = 68) and from 25 healthy children (n = 25). The fecal microbiota, and short chain fatty acids (SCFA) were measured. Results: The microbiota of patients with IF had a lower bacterial load (p = 0.003), Shannon diversity index (p&lt;0.001), taxon evenness (p&lt;0.001) and richness (p = 0.006) than healthy controls. Patients with surgical IF had lower α‐diversity (p&lt;0.039) than those with functional IF. Patients with IF had less propionic and butyric acid (p&lt;0.001), and more D and L‐lactate than healthy controls (p&lt;0.001). The percentage of calories supplied by PN (%PN) was negatively associated with microbiota diversity and influenced SCFA profile. IF patients had more Escherichia‐Shigella (p = 0.006), Cronobacter (p = 0.001) and Staphylococcus (OTU 14, p&lt;0.001) and less Faecalibacterium (p&lt;0.001) and Ruminococcus 1 and 2 (p&lt;0.001). Duration of PN (R2 = 6%, p = 0.005), % of calories from PN (R2 = 6%, p = 0.005) and fiber intake (R2 = 5%, p = 0.011) were predictive of microbiota community structure. A higher intake of enteral nutrition was associated with a microbiota composition and function closer to that of the healthy status. Conclusions: The microbiota composition and its diet‐related function are altered in pediatric IF, with profound depletion of beneficial SCFA and species, and supraphysiological increase of potentially harmful pathobionts. The influence of this compositional and functional microbial dysbiosis on patients’ clinical outcomes and management warrants further exploration