Children whose mothers experience a less diverse gut microbiome during pregnancy may be at increased risk of developing metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, later in life. Emerging research suggests a potential pathway to mitigate this risk: a naturally occurring compound produced by beneficial gut bacteria. A study conducted at the University of Oklahoma Health Sciences Center found that offspring of mice given indole, a compound created when gut bacteria break down the amino acid tryptophan, exhibited significantly lower rates of fatty liver disease, even when challenged with a high-fat, high-sugar diet.
MASLD is a growing concern, affecting an estimated 30% of obese children and 10% of children without obesity. The disease often remains undetected until symptoms related to liver dysfunction emerge, making early prevention crucial. “The disease in children is silent and typically isn’t discovered until a parent seeks help for their child for liver-related symptoms,” explained 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.
The Gut-Liver Connection
The study, published in the journal eBioMedicine, investigated the influence of the maternal microbiome on offspring liver health. Researchers fed female mice a Western-style diet – high in fat and sugar – throughout pregnancy and lactation. A subset of these mice also received indole supplementation. After weaning, the offspring were initially placed on a standard diet before being transitioned to a Western-style diet to promote the development of MASLD. The rationale behind this approach stems from the understanding that offspring inherit their microbiome from their mothers, and a mother’s diet can significantly shape the infant’s gut bacterial composition.
The results demonstrated a clear protective effect of indole. Offspring born to mothers who received indole exhibited healthier livers, reduced weight gain, improved blood sugar control, and smaller fat cells, even after exposure to the unhealthy diet. Researchers also observed activation of the acyl hydrocarbon receptor (AHR), a gut pathway known to have protective functions.
Ceramides and Microbiome Transfer
Further analysis revealed specific changes in lipid metabolism within the liver. The study found no increase in harmful long-chain ceramides, while levels of beneficial very long-chain ceramides increased in the offspring of indole-treated mothers. Ceramides are a class of lipids that accumulate in the liver during MASLD, and different types have varying effects on liver health.
To further validate the role of the microbiome, the researchers performed a microbiome transfer experiment. Gut bacteria from the protected offspring were transplanted into mice that had not received indole. Remarkably, these recipient mice also experienced less liver damage, strongly suggesting that the microbiome itself played a critical protective role. This finding underscores the potential for manipulating the gut microbiome to influence liver health.
Implications for Human Health and Future Research
While this research was conducted in mice, the findings offer promising avenues for preventing MASLD in humans. Currently, weight loss remains the only effective treatment for pediatric MASLD once the disease is established, and there are no approved medications. “Anything we can do to improve the mother’s microbiome may help prevent the development of MASLD in the offspring,” said Karen Jonscher, Ph.D., associate professor of biochemistry and physiology in the OU College of Medicine. “That would be far better than trying to reverse the disease once it has already progressed.”
The study highlights the importance of maternal diet and gut health during pregnancy and lactation. Indole is produced when gut bacteria metabolize tryptophan, an amino acid found in foods like turkey, nuts, and seeds. A diet rich in these foods may support a healthy gut microbiome and potentially reduce the risk of MASLD in offspring. However, more research is needed to determine whether similar effects can be achieved in humans.
Recent research, including a study published in Immunity, further supports the link between maternal diet, the gut microbiome, and offspring health, demonstrating that a high-fiber diet can promote microbiota that influence immune development. A review in Nature emphasizes that parental diet can alter offspring health through changes in the gut microbiome and epigenetic modifications. These changes can affect the offspring’s predisposition to various non-communicable diseases, including those related to metabolic and immune function.
The influence of the maternal microbiome extends beyond the immediate postnatal period. The gut-germline axis, referring to the communication between the gut microbiome and the gametes (eggs and sperm), and the gut-neonatal axis, describing the impact of the maternal microbiome on the developing infant, are both critical pathways through which dietary changes can have long-lasting effects on offspring health. The research underscores the need for translational studies investigating the benefits of parental dietary interventions, potentially using personalized approaches, to reduce the incidence of non-communicable diseases across generations.
Further research is needed to determine the optimal strategies for modulating the maternal microbiome to prevent MASLD and other chronic diseases in children. However, these findings provide a compelling rationale for prioritizing maternal gut health as a key component of preventative pediatric care.
