Summary:
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver condition worldwide, ranging from fat accumulation in the liver to inflammation, fibrosis, and metabolic dysfunction-associated steatohepatitis. It affects around 10% of children in the U.S. and up to one-third of those with obesity, yet the reasons for its prevalence in paediatric populations remain poorly understood. Maternal obesity and poor diet have been linked to early liver injury in offspring, suggesting that risk may begin in utero. Early-life gut microbiome development is influenced by maternal microbial exposure during birth and breastfeeding. Maternal Western-style diets can disrupt the offspring microbiome, with effects persisting even after a healthy diet is adopted. Deficiencies in microbe-derived tryptophan metabolites, including indole (Ind) and indole-3-acetic acid (I3A), are associated with metabolic dysfunction. These compounds activate the aryl hydrocarbon receptor (AHR), a protein that helps regulate detoxification, the immune system, gut health, and liver inflammation. Supplementation with these metabolites has been shown to reduce liver fat and improve gut barrier function. This study investigated whether maternal supplementation with indole metabolites during gestation and lactation influences offspring microbiome development and protects against later MASLD. Mother mice were given Ind or I3A during pregnancy and breastfeeding. Their offspring were later fed a Western-style diet to assess their response. Experiments also tested whether transferring gut bacteria from these offspring to other animals could pass on protective effects. Additional lab studies used human liver cells to examine how indoles and certain fat molecules influence liver scarring. Maternal indole supplementation had long-lasting protective effects in offspring, even after exposure to a Western-style diet. Offspring gained less weight, had reduced fat accumulation in the liver, decreased activation of liver cells that drive scarring, and less fibrosis. Indole exposure around birth activated AHR in the gut and liver and increased beneficial fat molecules in the liver by suppressing specific enzymes. Transferring gut bacteria from these offspring provided similar protective effects in recipients. Lab studies confirmed that indoles and these fat molecules directly reduce liver scarring, dependent on AHR activity. Overall, this study suggests that giving indoles to mothers during the perinatal period may help protect children from developing diet-related liver disease by shaping the gut microbiome, activating AHR, and modifying liver fat metabolism, highlighting a potential early-life strategy to prevent paediatric MASLD.
Abstract:
Background: Disruptions in early-life gut microbiota and metabolites associated with maternal Western-style diet (WD) during critical windows of development are linked to metabolic and inflammatory diseases in offspring, including metabolic dysfunction-associated steatotic liver disease (MASLD) in later life. These disturbances can alter microbial metabolite production, such as tryptophan derivatives, which are crucial for immune and metabolic regulation. However, the specific effects of maternal supplementation with tryptophan metabolites on offspring gut microbiome maturation and MASLD risk remain unexplored. Methods: WD-fed mouse dams were supplemented with microbial metabolites indole (Ind) or indole-3-acetic acid (I3A) during gestation and lactation; male offspring were weaned to chow diet for 9 weeks, followed by a 4-week WD challenge. Fecal microbiota transfer (FMT) was performed from offspring to naïve recipients, followed by a 4-week WD challenge. Human LX-2 stellate cells were used to study mechanisms for indole and very long-chain (VLC) ceramide effects on TGF-β-induced fibrosis. Findings: Maternal supplementation with Ind or I3A had long-term protective effects in adult WD-challenged offspring against excess weight gain, steatosis, stellate cell activation, and fibrosis. Perinatal exposure to Ind or I3A activated offspring aryl hydrocarbon receptor (AHR) signalling in gut and liver, which trans-repressed known and new target genes, including ceramidases Asah2 and Acer3, leading to increased VLC ceramides. FMT from offspring with perinatal exposure to Ind protected recipients from WD-induced fibrogenesis and increased beneficial VLC ceramides in recipient livers. In vitro, LX-2 stellate cells cultured with Ind or VLC ceramides demonstrated an anti-fibrotic effect, which was abolished by AHR inhibition. Interpretation: Maternal indole supplementation, through sustained activation of AHR in offspring gut and liver and an increase in hepatic VLC ceramides, prevents diet-induced MASLD and fibrosis in offspring, offering a novel therapeutic pathway for prevention of paediatric MASLD.
Article Publication Date: 07/01/2026
DOI: 10.1016/j.ebiom.2025.106098
