Reprogramming offspring liver health: maternal indole supplementation as a preventive strategy against MASLD

Area of Science:

• Microbiology
• Metabolomics
• Hepatology
• Developmental Biology

Background:

• Maternal Western-style diet (WD) disrupts early-life gut microbiota, increasing offspring risk for metabolic and inflammatory diseases like MASLD.
• Tryptophan derivatives, microbial metabolites crucial for immune and metabolic regulation, are affected by these disruptions.
• The impact of maternal tryptophan metabolite supplementation on offspring gut microbiome and MASLD risk is unknown.

Purpose of the Study:

• To investigate the effects of maternal indole (Ind) or indole-3-acetic acid (I3A) supplementation on offspring gut microbiome maturation and MASLD development.
• To explore the underlying mechanisms of protection against diet-induced MASLD and liver fibrosis.

Main Methods:

• Mouse dams on WD were supplemented with Ind or I3A during gestation and lactation.
• Offspring were challenged with WD, and fecal microbiota transfer (FMT) was performed.
• Human LX-2 stellate cells were used to assess mechanisms of indole and very long-chain (VLC) ceramide effects on fibrosis.

Main Results:

• Maternal Ind or I3A supplementation conferred long-term protection against weight gain, steatosis, and liver fibrosis in adult offspring.
• Perinatal exposure activated offspring aryl hydrocarbon receptor (AHR) signaling, increasing hepatic VLC ceramides.
• FMT from exposed offspring protected recipients from WD-induced fibrogenesis; in vitro studies confirmed anti-fibrotic effects of Ind and VLC ceramides.

Conclusions:

• Maternal indole supplementation, via sustained AHR activation and increased hepatic VLC ceramides, prevents diet-induced MASLD and fibrosis.
• This offers a novel therapeutic strategy for preventing pediatric MASLD.
• The study highlights the critical role of early-life microbial metabolites in long-term metabolic health.