Impaired liver function during pregnancy may increase risk of childhood obesity

Impaired liver function during pregnancy may alter gut bacteria composition and increase the risk of obesity in children, according to results presented at The Society for Endocrinology Annual Conference. In a rodent of model of the most common liver disease in pregnancy, the composition of gut bacteria in offspring was altered and liver function impaired, particularly when they were fed a Western-style, high-fat diet. These findings suggest that children at risk should maintain a healthy diet and that interventions to alter gut bacteria may help reduce childhood obesity rates in the future.

The most common liver disease in pregnancy, intrahepatic cholestasis (ICP), reduces the release of digestive fluid bile from the liver causing bile acids to build up in the blood, impairing liver function, causing severe itching for the mother and increasing risks of stillbirth and preterm birth for the baby. Previous studies suggest that children of women with ICP are more likely to develop childhood obesity. Growing evidence suggests the importance of the gut microbiome for good metabolic health and that altered composition can lead to impaired metabolism and weight gain. No previous studies have investigated the effects of ICP during pregnancy on the gut microbiome of either mothers or their children. Understanding how ICP may lead to obesity in children could help prevent the risk of developing this serious and life-limiting condition.

Dr Caroline Ovadia from King’s College London and colleagues investigated how gut microbiota are affected in the offspring of a mouse model of ICP. The results reported that the offspring had a different gut microbiome composition and liver function, particularly when fed a high-fat diet, which could contribute to impaired metabolism and increase risk of obesity.

Dr Ovadia comments, “These findings further suggest that health during pregnancy can have long-term health effects on children, and in this case how gut microbiome alterations may increase the risk of obesity in children on a Western style, high-fat diet.”

The results suggest that mice born to mothers with ICP, or other liver diseases, may benefit from maintaining a healthy diet and should avoid fatty foods. These findings also suggest that targeting microbiome composition with treatment strategies in pregnant women, such as using pre-biotics or pro-biotics, could help prevent the risk of child obesity.

“Understanding changes in composition of the gut microbiome and their effects may provide new ways of diagnosing patients at particular risk of obesity before it occurs. We could then develop personalised medicine and target appropriate treatments to alter gut bacteria accordingly,” Dr Ovadia adds.

Despite some similarities, mouse and human microbiome composition differs, therefore these findings may not accurately represent outcomes in humans. However, determining effects on human microbiomes can be difficult as it is harder to obtain samples from the gut, and control diet and environment. Dr Ovadia is now examining the composition of stool samples from babies to establish whether they differ from normal if their mother had ICP. She hopes to determine if any treatments are able to alter and normalise the composition of the microbiome, with the aim of reducing the risk of childhood obesity.

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Conference abstract, experimental study, animals

Abstract

P209

Maternal diet-induced cholestasis programmes murine offspring metabolic impairment on feeding a Western diet, with altered intestinal metabolites and microbiota in the female offspring

Caroline Ovadia, Konstantina Spagou, Alvaro Perdones-Montero, Ann Smith, Georgia Papacleovoulou, Peter Dixon, Elaine Holmes, Julian Marchesi, Catherine Williamson

Background

The 16-year-old children of mothers with intrahepatic cholestasis of pregnancy demonstrate increased adiposity, dyslipidaemia, and males have raised fasting insulin. Similarly, the offspring of cholestatic pregnant mice have impaired glucose tolerance and dyslipidaemia when challenged with a Western diet. Female offspring have a more marked phenotype than males.

Bile influences microbial growth, thus intestinal bile acid exposure in pregnancy may contribute to metabolic impairments observed. We hypothesise that the offspring of cholestatic pregnancies develop an abnormal gut bacterial and metabolite composition, contributing to the offspring’s phenotype.

Methods

C57BL/6 female mice were fed normal chow or 0.5% cholic acid-supplemented diets and mated. Their offspring were fed normal chow or Western diets. Ultra-performance liquid chromatography – mass spectrometry was used to assess the caecal metabonome. Metataxonomics was performed to determine the caecal microbiota. Results were compared using OPLS-DA, PCA, NMDS, and T-tests with Benjamini-Hochberg correction for multiple measures.

Results

The offspring microbiota was significantly affected by maternal and neonatal diet, with a sex difference in bacterial composition revealed in the pups of mothers fed cholic acid, when fed a Western diet. The female offspring of cholic acid-fed mothers had a higher abundance of Alistipes, a bile acid-resistant member of the Bacteroidetes phylum, than males. This group had lower caecal bile acids (p=0.036) (particularly deoxycholic acid, cholic acid and ω-muricholic acid) than offspring of normal chow-fed mothers when challenged with a Western diet.

Conclusions

Maternal cholic acid feeding results in increases in bile-resistant bacteria in the caecum of female offspring. A gender difference in the microbiome and bile acid content of the caecum is revealed by a Western diet. Together, these findings demonstrate how the establishment of the offspring gut microbiome, and associated metabonome, is influenced by an altered maternal environment, contributing to increased long-term risk of metabolic impairment.

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