Lucien F. Harthoorn

Obesity in pregnancy: implications for the mother and lifelong health of the child. A consensus statement

Obesity among pregnant women is becoming one of the most important womens health issues. Obesity is associated with increased risk of almost all pregnancy complications: gestational hypertension, preeclampsia, gestational diabetes mellitus, delivery of large-for-GA infants, and higher incidence of congenital defects all occur more frequently than in women with a normal BMI. Evidence shows that a child of an obese mother may suffer from exposure to a suboptimal in utero environment and that early life adversities may extend into adulthood. In September 2009, ILSI Europe convened a workshop with multidisciplinary expertise to review practices and science base of health and nutrition of obese pregnant women, with focus on the long-term health of the child. The consensus viewpoint of the workshop identified gaps and gave recommendations for future research on gestational weight gain, gestational diabetes, and research methodologies. The evidence available on short- and long-term health impact for mother and child currently favors actions directed at controlling prepregnancy weight and preventing obesity in women of reproductive ages. More randomized controlled trials are needed to evaluate the effects of nutritional and behavioral interventions in pregnancy outcomes. Moreover, suggestions that maternal obesity may transfer obesity risk to child through non-Mendelian (e.g. epigenetic) mechanisms require more long-term investigation.

Metabolic imprinting, programming and epigenetics - a review of present priorities and future opportunities

Metabolic programming and metabolic imprinting describe early life events, which impact upon on later physiological outcomes. Despite the increasing numbers of papers and studies, the distinction between metabolic programming and metabolic imprinting remains confusing. The former can be defined as a dynamic process whose effects are dependent upon a critical window(s) while the latter can be more strictly associated with imprinting at the genomic level. The clinical end points associated with these phenomena can sometimes be mechanistically explicable in terms of gene expression mediated by epigenetics. The predictivity of outcomes depends on determining if there is causality or association in the context of both early dietary exposure and future health parameters. The use of biomarkers is a key aspect of determining the predictability of later outcome, and the strengths of particular types of biomarkers need to be determined. It has become clear that several important health endpoints are impacted upon by metabolic programming/imprinting. These include the link between perinatal nutrition, nutritional epigenetics and programming at an early developmental stage and its link to a range of future health risks such as CVD and diabetes. In some cases, the evidence base remains patchy and associative, while in others, a more direct causality between early nutrition and later health is clear. In addition, it is also essential to acknowledge the communication to consumers, industry, health care providers, policy-making bodies as well as to the scientific community. In this way, both programming and, eventually, reprogramming can become effective tools to improve health through dietary intervention at specific developmental points.

A potential role for regulatory T-cells in the amelioration of DSS induced colitis by dietary non-digestible polysaccharides

Inflammatory bowel diseases (IBD) including ulcerative colitis (UC) and Crohns disease (CD) are chronic relapsing inflammatory disorders of the gastrointestinal tract. The interaction between a disturbed microbial composition, the intestinal mucosal barrier and the mucosal immune system plays an important role in IBD and its chronicity. It has been indicated that due to the altered microbial composition the balance between T regulatory cells (Treg) and T helper cells (Th) 17 is disturbed, leading to an inflammatory state. The present study shows that oral intake of a specific multi fibre mix (MF), designed to match the fibre content of a healthy diet, counteracts IBD-like intestinal inflammation and weight loss in dextran sodium sulphate treated mice. This reduction in inflammation might be brought about, at least in part, by the MF-induced decrease in inflammatory cytokines, increase in IL-10 and the relative increase in Treg cells in the mesenteric lymph nodes (MLN). Moreover, the Treg percentage in the MLN correlates with the percentage of tolerogenic lamina propria derived CD103+RALDH+dendritic cells in the MLN, suggesting that these play a role in the observed effects. In children with CD exclusive enteral nutrition (EEN) is a widely used safe and effective therapy. Optimizing enteral nutritional concepts with the tested fibre mix, know to modulate the gut microbiota composition, SCFA production and inflammatory status (as indicated by the present study) could possibly further improve efficacy in inducing remission.

Effects on growth and tolerance and hypoallergenicity of an amino acid-based formula with synbiotics

Background:To evaluate the effects of an amino acid–based formula (AAF) with synbiotics on growth and tolerance in healthy infants. The hypoallergenicity of this AAF with synbiotics was evaluated in subjects with cow’s milk allergy (CMA).Methods:Study 1: 115 full-term, healthy infants randomly received an AAF with synbiotics or a commercially available AAF for 16 wk. Subjects’ weight, length, and head circumference were primary outcome measures. Stool characteristics and gastrointestinal (GI) symptoms were secondary outcome measures. Clinical examinations, dietary intake, clinical laboratory results, and adverse events were recorded. Study 2: hypoallergenicity of the AAF with synbiotics was evaluated in 30 infants and children with immunoglobulin E (IgE)–mediated CMA using a double-blind, placebo-controlled food challenge, and a 7-d feeding period.Results:Study 1: comparable results in growth parameters and tolerance were observed for both groups. Minimal differences were observed in stool characteristics and GI symptoms throughout the study. Study 2: all 30 subjects with IgE-mediated CMA completed the study with no allergic reactions detected to challenges.Conclusion:These studies demonstrate that an AAF with synbiotics is safe and well tolerated and promotes normal growth when fed to healthy full-term infants as the sole source of nutrition and is hypoallergenic in subjects with CMA.

Elemental diet decreases inflammation and improves symptoms in adult eosinophilic oesophagitis patients.

Eosinophilic oesophagitis (EoE) is a chronic disease, driven by food allergens. Elemental diets are effective for the management of children with EoE, but studies on the effect of elemental diets in adults are scarce and poor palatability challenges dietary adherence.

Synbiotics‐supplemented amino acid‐based formula supports adequate growth in cow's milk allergic infants

Children with cows milk allergy (CMA) are at risk for inadequate nutritional intake and growth. Dietary management of CMA, therefore, requires diets that are not only hypoallergenic but also support adequate growth in this population. This study assessed growth of CMA infants when using a new amino acid‐based formula (AAF) with prebiotics and probiotics (synbiotics) and evaluated its safety in the intended population.

Post-sensitization administration of non-digestible oligosaccharides and Bifidobacterium breve M-16V reduces allergic symptoms in mice.

To support dietary management of severe cows milk allergic infants, a synbiotic mixture of non‐digestible oligosaccharides and Bifidobacterium breve M‐16V (B. breve) was designed from source materials that are completely cows milk‐free. It was investigated whether this specific synbiotic concept can reduce an established food allergic response in a research model for hens egg allergy. Mice were orally sensitized once a week for 5 weeks to ovalbumin (OVA) using cholera toxin (CT) as an adjuvant. Non‐sensitized mice received CT in PBS only. Sensitized mice were fed a control diet or a diet enriched with short‐chain‐ (scFOS) and long‐chain fructo‐oligosaccharides (lcFOS), B. breve or scFOSlcFOS + B. breve for 3 weeks starting after the last sensitization. Non‐sensitized mice received the control diet. Anaphylactic shock symptoms, acute allergic skin responses and serum specific IgE, mMCP‐1 and galectin‐9 were measured upon OVA challenge. Activated Th2‐, Th1‐cells and regulatory T‐cells were quantified in spleen and mesenteric lymph nodes (MLN) and cytokine profiles were analyzed. Short chain fatty acids (SCFA) were measured in ceacal samples. The acute allergic skin response was reduced in mice fed the scFOSlcFOS + B. breve diet compared to mice fed any of the other diets. A reduction in mast cell degranulation (mMCP‐1) and anaphylactic shock symptoms was also observed in these mice. Unstimulated splenocyte cultures produced increased levels of IL10 and IFNg in mice fed the scFOSlcFOS + B. breve diet. Correspondingly, increased percentages of activated Th1 cells were observed in the spleen. Allergen‐specific re‐stimulation of splenocytes showed a decrease in IL5 production. In summary; post‐sensitization administration of scFOSlcFOS + B. breve was effective in reducing allergic symptoms after allergen challenge. These effects coincided with changes in regulatory and effector T‐cell subsets and increases in the SCFA propionic acid. These results suggest immune modulatory benefits of dietary intervention with a unique combination of scFOSlcFOS + B. breve in established food allergy. Whether these effects translate to human applications is subject for ongoing clinical studies.To support dietary management of severe cows milk allergic infants, a synbiotic mixture of non-digestible oligosaccharides and Bifidobacterium breve M-16V (B. breve) was designed from source materials that are completely cows milk-free. It was investigated whether this specific synbiotic concept can reduce an established food allergic response in a research model for hens egg allergy. Mice were orally sensitized once a week for 5 weeks to ovalbumin (OVA) using cholera toxin (CT) as an adjuvant. Non-sensitized mice received CT in PBS only. Sensitized mice were fed a control diet or a diet enriched with short-chain- (scFOS) and long-chain fructo-oligosaccharides (lcFOS), B. breve or scFOSlcFOS + B. breve for 3 weeks starting after the last sensitization. Non-sensitized mice received the control diet. Anaphylactic shock symptoms, acute allergic skin responses and serum specific IgE, mMCP-1 and galectin-9 were measured upon OVA challenge. Activated Th2-, Th1-cells and regulatory T-cells were quantified in spleen and mesenteric lymph nodes (MLN) and cytokine profiles were analyzed. Short chain fatty acids (SCFA) were measured in ceacal samples. The acute allergic skin response was reduced in mice fed the scFOSlcFOS + B. breve diet compared to mice fed any of the other diets. A reduction in mast cell degranulation (mMCP-1) and anaphylactic shock symptoms was also observed in these mice. Unstimulated splenocyte cultures produced increased levels of IL10 and IFNg in mice fed the scFOSlcFOS + B. breve diet. Correspondingly, increased percentages of activated Th1 cells were observed in the spleen. Allergen-specific re-stimulation of splenocytes showed a decrease in IL5 production. In summary; post-sensitization administration of scFOSlcFOS + B. breve was effective in reducing allergic symptoms after allergen challenge. These effects coincided with changes in regulatory and effector T-cell subsets and increases in the SCFA propionic acid. These results suggest immune modulatory benefits of dietary intervention with a unique combination of scFOSlcFOS + B. breve in established food allergy. Whether these effects translate to human applications is subject for ongoing clinical studies.

Esophageal and Small Intestinal Mucosal Integrity in Eosinophilic Esophagitis and Response to an Elemental Diet

Objectives:The esophageal mucosal integrity is impaired in eosinophilic esophagitis (EoE) and it has been suggested that the duodenal permeability is increased. The absence of food allergens may restore the integrity. The aims of this study were to assess duodenal permeability in EoE and to evaluate the effect of an elemental diet on the esophageal and duodenal integrity.Methods:In this prospective study 17 adult EoE patients and 8 healthy controls (HC) were included. Esophageal biopsy specimens were sampled before and after 4 weeks of elemental diet to measure eosinophil counts and gene expression of tight junction and barrier integrity proteins. Esophageal and duodenal impedance were measured by electrical tissue impedance spectroscopy and Ussing chambers were used to measure transepithelial resistance (TER) and transepithelial molecule flux. Small intestinal permeability was measured using a test, measuring lactulose/mannitol (L/M) ratios.Results:In EoE patients, the esophageal but not the duodenal integrity was impaired, compared with HC. We observed no significant difference between L/M ratios of HC and EoE patients. After diet, eosinophil counts decreased significantly, which was paralleled by normalization of esophageal impedance and transepithelial molecule flux. The esophageal TER improved significantly, but did not reach values seen in HC. Esophageal expression of genes encoding for barrier integrity proteins filaggrin and desmoglein-1 was impaired at baseline and restored after diet.Conclusions:An elemental diet restores esophageal integrity, suggesting that it is at least partly secondary to allergen exposure. Duodenal integrity seems not to be affected in EoE, and possibly plays a minor role in its pathophysiology.

A synbiotic-containing amino acid-based formula improves gut microbiota in non-IgE-mediated allergic infants

BackgroundPrebiotics and probiotics (synbiotics) can modify gut microbiota and have potential in allergy management when combined with amino-acid-based formula (AAF) for infants with cow’s milk allergy (CMA).MethodsThis multicenter, double-blind, randomized controlled trial investigated the effects of an AAF-including synbiotic blend on percentages of bifidobacteria and Eubacterium rectale/Clostridium coccoides group (ER/CC) in feces from infants with suspected non-IgE-mediated CMA. Feces from age-matched healthy breastfed infants were used as reference (healthy breastfed reference (HBR)) for primary outcomes. The CMA subjects were randomized and received test or control formula for 8 weeks. Test formula was a hypoallergenic, nutritionally complete AAF including a prebiotic blend of fructo-oligosaccharides and the probiotic strain Bifidobacterium breve M-16V. Control formula was AAF without synbiotics.ResultsA total of 35 (test) and 36 (control) subjects were randomized; HBR included 51 infants. At week 8, the median percentage of bifidobacteria was higher in the test group than in the control group (35.4% vs. 9.7%, respectively; P<0.001), whereas ER/CC was lower (9.5% vs. 24.2%, respectively; P<0.001). HBR levels of bifidobacteria and ER/CC were 55% and 6.5%, respectively.ConclusionAAF including specific synbiotics, which results in levels of bifidobacteria and ER/CC approximating levels in the HBR group, improves the fecal microbiota of infants with suspected non-IgE-mediated CMA.

Amino acid-based formula affects the gastrointestinal cytokine milieu of children with non-IgE mediated cow’s milk allergy.

Food Allergy (FA) presents a significant health and economic burden in the western world. Children with non-IgE mediated cows milk allergy (CMA) are being increasingly seen in clinic. Diagnosis is largely based on delayed onset of symptoms, primarily affecting the gastrointestinal (GI) mucosa. Treatment involves an elimination diet supplemented with amino acid-based formula (AAF) which in some children results in effective symptom relief. To understand the beneficial effects of AAF at the molecular level, herein we characterized the GI cytokine milieu ex vivo from children with or without AAF in their elimination diets.