Kati Mokkala

Increased intestinal permeability, measured by serum zonulin, is associated with metabolic risk markers in overweight pregnant women

BACKGROUND Increased intestinal permeability with subsequent metabolic endotoxemia, i.e., elevated circulating levels of bacterial lipopolysaccharide, LPS, has been introduced as a novel initiator of obesity related metabolic disturbances in non-pregnant individuals. The objective was to investigate the extent to which intestinal permeability, measured by serum zonulin concentration, is related to metabolic endotoxemia and metabolic risk markers in overweight pregnant women. METHODS This was a cross-sectional study including 100 pregnant overweight women in early pregnancy. Serum zonulin was analyzed using ELISA, and markers for metabolic endotoxemia (LPS), inflammation (high-sensitive C-reactive protein and glycoprotein acetylation GlyA), glucose metabolism (fasting glucose and insulin), and lipid metabolism were measured. RESULTS Higher serum zonulin concentration associated positively with LPS (P=0.02), inflammatory markers (P<0.001), insulin (P<0.001), insulin resistance (P<0.001), and triglycerides (P=0.001), and negatively with insulin sensitivity (P=0.001) (ANOVA with Tukeys corrections or Kruskal-Wallis nonparametric test with Bonferroni correction for zonulin quartiles). All the observed associations were confirmed (P<0.015) in a linear regression model adjusted with potential confounding factors. Both LPS and GlycA showed positive relationship with insulin resistance, serum insulin, triglycerides, total and LDL-cholesterol and negative relationship with insulin sensitivity (P≤0.03) in the univariate linear regression. Positive relationship was also found between LPS and HDL-cholesterol (P=0.03). CONCLUSIONS Our findings suggest that increased serum zonulin concentration, i.e., increased intestinal permeability, contributes to metabolic endotoxemia, systemic inflammation, and insulin resistance in overweight pregnant women. By reinforcing intestinal barrier, it may be possible to manipulate maternal metabolism during pregnancy with subsequent health benefits.

Bifidobacterium lactis 420 and fish oil enhance intestinal epithelial integrity in Caco-2 cells

Increased intestinal permeability is a predisposing factor for low-grade inflammation-associated conditions, including obesity and type 2 diabetes. Dietary components may influence intestinal barrier integrity. We hypothesized that the dietary supplements Bifidobacterium lactis 420, Lactobacillus rhamnosus HN001, and fish oil have beneficial impacts on intestinal barrier integrity. In addition, we hypothesized that the coadministration of these components results in synergistic benefits to the integrity of the intestinal barrier. To study this, we investigated the impact of cell-free culture supernatant from dietary supplements B lactis 420 and L rhamnosus HN001, and fish oil, separately and in combination, on intestinal permeability in a CaCo-2 cell model. Administered separately, both B lactis 420 supernatant and fish oil significantly increased the integrity of the intestinal epithelial barrier, as determined by an increase in transepithelial electrical resistance (TEER), whereas L rhamnosus did not. The TEER increase with B lactis 420 was dose dependent. Interestingly, a combination of B lactis 420 supernatant and fish oil negated the increase in TEER of the single components. mRNA expression of tight junction proteins, measured by real-time quantitative polymerase chain reaction, was not altered, but the mRNA expression of myosin light chain kinase increased after fish oil treatment. To conclude, single dietary components, namely, B lactis 420 and fish oil, induced beneficial effects on intestinal barrier integrity in vitro, whereas a combination of 2 beneficial test compounds resulted in a null effect.

Gut microbiota aberrations precede diagnosis of gestational diabetes mellitus

This study included 75 overweight and obese women without GDM at early pregnancy. Inclusion criteria were ≤ 17 weeks of gestation, body mass index (BMI) ≥ 25 and age 18–45 years. Exclusion criteria included chronic metabolic and gastrointestinal diseases including celiac disease, inflammatory bowel diseases and diabetes. Gut microbiota composition was analysed at a mean of 12.9 (SD 2.5) weeks of gestation through 16S RNA gene sequencing and the QIIME pipeline. On the basis of the sequences, a total of 731 operating taxonomic units (OTUs) were detected and the relative abundance was determined. The bacteria with a relative abundance > 1% were considered to be reliable and were selected for further analysis. Fasting plasma glucose concentration and hs-CRP were measured in accreted laboratory with standard methods. Daily intakes of fat and fibre were calculated from three-day food diaries using computerized software (Aivo diet 2.0.2.3, Aivo, Turku, Finland). The GDM was diagnosed on the basis of a 2 h 75 g oral glucose tolerance test (OGTT) if one or more values were at or above the threshold level: 0 h ≥ 5.3, 1 h ≥ 10.0, 2 h ≥ 8.6 mmol/l at a mean 25.5 (SD 2.2) weeks of gestation. All procedures involving human subjects were approved by the Ethics Committee of the Hospital District of Southwest Finland. Abbreviations AUC The area under curve GDM Gestational diabetes hs-CRP High sensitive CRP OR Odds ratio OTUs Operational taxonomic units

Evaluation of serum zonulin for use as an early predictor for gestational diabetes

Diet has an important role in regulating intestinal permeability and subsequently the risk for metabolic disorders. In this observational study, we examined whether serum intestinal permeability marker zonulin, could be used as a predictor for gestational diabetes mellitus (GDM). Serum zonulin concentration was measured in early pregnancy in overweight or obese pregnant women (n=88) at risk for developing GDM. Serum zonulin was associated with higher odds of GDM (adjusted OR for 1 ng ml−1 increase in zonulin: 1.08, 95% CI: 1.02–1.15; P=0.009), diagnosed by a 2-h 75-g oral glucose tolerance test at late pregnancy. The optimal cutoff value was 43.3 ng ml−1, with sensitivity of 88% (95% CI: 71–100%) and specificity of 47% (95% CI: 33–58%). The area under the ROC-curve was 0.67 (95% CI: 0.54–0.81). Our results show an association between increased early-pregnancy serum zonulin concentration and GDM, suggesting zonulin as a possible predictor for GDM.

Opportunities for probiotics and polyunsaturated fatty acids to improve metabolic health of overweight pregnant women

Overweight during pregnancy predisposes both the mother and foetus to health complications. Maternal complications include gestational diabetes, obstetric problems and type 2 diabetes later in life. Complications for the offspring are not only restricted to the foetal period or birth, such as prematurity and foetal macrosomia, but may also have long-term metabolic health implications through the mechanism of early nutrition programming. One of the key metabolic components characterising overweight in the non-pregnant state is low-grade inflammation manifested by elevated levels of circulatory pro-inflammatory cytokines. In pregnancy, in addition to adipose tissue and placenta, inflammatory response may originate from the gut. The extent to which overweight induces metabolic maladaptation during pregnancy and further compromises maternal and child health is currently poorly understood. In this review, we evaluate recent scientific literature and describe the suggested links between overweight, gut and low-grade inflammation associated metabolic disorders. We focus on overweight pregnant women and gestational diabetes, and discuss how specific dietary factors, probiotics and long-chain polyunsaturated fatty acids (fish oil), might confer health benefits in combatting against metabolic risk factors.

Body composition measurement by air displacement plethysmography in pregnancy: comparison of predicted versus measured thoracic gas volume

OBJECTIVES Body composition measurements with air displacement plethysmography (ADP) define body volume, which must be corrected for thoracic gas volume (TGV). We hypothesized that physiologic changes owing to pregnancy could affect the accuracy of predicted TGV and introduce errors into body composition measurements. METHODS We investigated the effect of measuring versus predicting TGV on the accuracy of body composition calculations measured with ADP in overweight and obese pregnant women. The fat and fat-free masses of 110 women were determined with ADP with predicted and measured TGV. RESULTS Measured TGV decreased from early to late pregnancy (P = 0.0002). Compared with measured TGV, predicted TGV was 6.3% higher during early gestation and 12.6% higher during late gestation (both P ≤ 0.001). The use of predicted instead of measured TGV in body composition calculations resulted in an overestimation of fat mass by 0.8% during the early stage, and 2.6% during the late stage of pregnancy (both P ≤ 0.001). CONCLUSIONS Measuring TGV increases the accuracy of body composition measurement by ADP in overweight and obese women, particularly during the late stage of pregnancy.

The impact of probiotics and n-3 long-chain polyunsaturated fatty acids on intestinal permeability in pregnancy: a randomised clinical trial

A disruption in intestinal barrier integrity may predispose individuals to metabolic aberrations, particularly during the vulnerable period of pregnancy. We investigated whether intestinal permeability, as measured by serum zonulin concentration, changes over the duration of pregnancy and whether this change is reflected in lipopolysaccharide (LPS) activity. Second, we tested in a randomised double-blind placebo controlled clinical trial the impact of consuming dietary probiotics and/or long chain polyunsaturated fatty acid (LC-PUFA) supplements in lowering serum zonulin concentration and LPS activity. The probiotic supplement was a combination of two bacteria, Bifidobacterium animalis ssp. lactis 420 and Lactobacillus rhamnosus HN001. This study included 200 overweight pregnant women participating in an on-going study; participants were randomised to consume either (1) probiotics, (2) LC-PUFA, (3) probiotics and LC-PUFA, or (4) placebo for each supplement. Blood samples were obtained at early, the baseline, and late pregnancy (mean 14 and 35 weeks of gestation, respectively). Serum zonulin concentration increased from early (mean (standard deviation): 62.7 (12.9) ng/ml) to late pregnancy by 5.3 (95%CI 3.7-6.9) ng/ml, and LPS activity increased from (0.16 (0.04) EU/ml) by 0.04 (95%CI 0.03-0.05) EU/ml. No differences among the intervention groups were detected in the change from early to late pregnancy in serum zonulin concentration (P=0.8) or LPS activity (P=0.2). The change in serum zonulin concentration during the pregnancy was associated with the weeks of follow up (r=0.25, P<0.001). Serum LPS activity was correlated with higher maternal weight gain (r=0.19, P=0.008). As a conclusion, intestinal permeability increased with the progression of pregnancy in overweight and obese women and was reflected in LPS activity. No efficacy of supplementation with probiotics and/or LC-PUFA was demonstrated in pregnancy-induced changes in serum zonulin concentration or LPS activity.