Studies in pregnant women indicate the maternal microbiome changes during pregnancy so as to benefit the mother and fetus. In contrast, disruption of the maternal microbiota around birth can compromise normal bacterial colonisation of the infant’s gastrointestinal tract. This may then inhibit development of the gut so as to increase susceptibility to inflammation and reduce barrier function. The impact of modulating fructose intake on the maternal microbiome through pregnancy is unknown, therefore we examined the effect of fructose supplementation on the maternal microbiome together with the immediate and next generation effects in the offspring. Wistar rat dams were divided into control and fructose fed groups that received 10% fructose in their drinking water from 8 weeks of age and throughout pregnancy (10–13 weeks). Maternal fecal and blood samples were collected pre-mating (9 weeks) and during early (gestational day 4–7) and late pregnancy (gestational day 19–21). We show supplementation of the maternal diet with fructose appears to significantly modulate the maternal microbiome, with a significant reduction in Lactobacillus and Bacteroides. In offspring maintained on this diet up to pregnancy and term there was a reduction in gene expression of markers of gut barrier function that could adversely affect its function. An exacerbated insulin response to pregnancy, reduced birth weight, but increased fat mass was also observed in these offspring. In conclusion dietary supplementation with fructose modulates the maternal microbiome in ways that could adversely affect fetal growth and later gut development.

The need to refine rodent models of human-related disease is now being recognized, in particular the rearing environment that can profoundly modulate metabolic regulation. Most studies on pregnancy and fetal development purchase and transport young females into the research facility, which after a short period of acclimation are investigated (Gen0). We demonstrate that female offspring (Gen1) show an exaggerated hyperinsulinemic response to pregnancy when fed a standard diet and with high fructose intake, which continues throughout pregnancy. Markers of maternal hepatic metabolism were differentially influenced, as the gene expression of acetyl-CoA-carboxylase was raised in Gen1 given fructose and controls, whereas glucose transporter 5 and fatty acid synthase expression were only raised with fructose. Gen1 rats weighed more than Gen0 throughout the study, although fructose feeding raised the percent body fat but not body weight. We show that long-term habituation to the living environment has a profound impact on the animal’s metabolic responses to nutritional intervention and pregnancy. This has important implications for interpreting many studies investigating the influence of maternal consumption of fructose on pregnancy outcomes and offspring to date.

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Maternal diet in pregnancy has been shown to affect offspring development but few studies have examined changes in the gut. Gut barrier dysfunction may allow components of the microbiota to pass into the circulation, which has been linked to the development of obesity and the metabolic syndrome. This study examined the effect of a maternal diet that is high in fructose on gut permeability markers in pregnant offspring. Female Wistar rats were placed on 10% fructose (F1) or water (W1) at 8 weeks of age and were mated at 10 weeks; the intervention continued throughout pregnancy. Female offspring continued on the same diet as their dams (W2, n=10 and F2, n=10) from 4 weeks of age, were mated at 10 weeks, and tissue was collected at gestational day 20. Ileum and jejunum expression of occludin (OCLN), claudin 3 (CLDN3) and zonulin 1 (ZO1) were used as markers of intestinal permeability. F2 pups had a lower birth weight but similar weights at 13 weeks of age compared with W2. F2 also had a significantly higher % fat mass and reduced gut length vs W2. Expression of ZO1 (W2=1.64±0.28; F2=0.64±0.09), OCLN (W2=1.27±0.15; F2=0.51±0.09), but not CLDN3 (W2=1.09±0.19; F2=2.15±0.45) was reduced in the jejunum (p<0.05) but not different in the ileum. A high fructose diet during pregnancy increases intestinal permeability in pregnant offspring. Further studies will examine the effect of the fructose diet on the microbiome during pregnancy.

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