Gut bacteria compound during pregnancy protects offspring from fatty liver disease

Children born to mothers who consume a high-fat, high-sugar diet during pregnancy and breastfeeding face a higher risk of developing fatty liver disease later in life. New research from the University of Oklahoma suggests that risk may be reduced: A study found that supplementing pregnant and lactating mice with a naturally occurring compound produced by healthy gut bacteria significantly lowered rates of fatty liver disease in their offspring as they aged.

The compound, called indole, is naturally made by healthy gut bacteria when they break down tryptophan, an amino acid found in foods such as turkey and nuts. The findings further a promising line of research into preventing a type of fatty liver disease known as metabolic dysfunction-associated steatotic liver disease (MASLD). While MASLD affects both adults and children, it tends to progress more rapidly in children and is strongly linked with diabetes.

The prevalence of MASLD in children is about 30% in those with obesity and about 10% in children without obesity. Unfortunately, the risk is higher if a mother is obese or consumes a poor diet. The disease in children is silent and typically isn't discovered until a parent seeks help for their child for liver-related symptoms."

Jed Friedman, Ph.D., director of the OU Health Harold Hamm Diabetes Center and professor of biochemistry and physiology in the OU College of Medicine

Friedman is a lead author of the study, published in the journal eBioMedicine, along with Karen Jonscher, Ph.D., associate professor of biochemistry and physiology in the OU College of Medicine. The researchers hypothesized that gut bacteria, known collectively as the microbiome, play an important role in the development of fatty liver disease.

To test that idea, they fed female mice a high-fat, high-sugar (Western-style) diet during pregnancy and lactation. Some of the mice were also given indole. After weaning, the offspring were raised on a normal diet before later being fed a Western-style diet to prompt the development of fatty liver disease.

"Because offspring inherit their microbiome from their mother, a poor maternal diet can shape the infant's microbiome in harmful ways," Friedman said.

Among offspring whose mothers received indole, researchers observed several encouraging outcomes. These mice maintained healthier livers, gained less weight, had lower blood sugar levels and smaller fat cells, even after exposure to a Western-style diet later in life. Researchers also saw activation of a protective gut pathway involving the acyl hydrocarbon receptor (AHR).

In addition, harmful liver fats known as long-chain ceramides were unchanged, while beneficial very long-chain ceramides increased. Perhaps most notably, when gut bacteria from these protected offspring were transferred to other mice that had not been given indole, those mice also showed reduced liver damage – further evidence that the microbiome itself plays a key role in protection.

While the findings are based on animal studies and more research is needed before applying them to humans, the study opens the door to new approaches for reducing the growing burden of MASLD through early prevention.

Except for weight loss, there currently are no approved drugs for the treatment of pediatric MASLD once it takes hold. "Anything we can do to improve the mother's microbiome may help prevent the development of MASLD in the offspring," Jonscher said. "That would be far better than trying to reverse the disease once it has already progressed."