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

Maternal supplementation with indole (Ind) or indole-3-acetic acid (I3A) during gestation and lactation had long-term protective effects in adult WD-challenged offspring against excess weight gain, steatosis, stellate cell activation, and fibrosis.

• WD-fed mouse dams were supplemented with Ind or I3A during gestation and lactation
• Male offspring were weaned to chow diet for 9 weeks followed by a 4-week WD challenge
• Protection was observed against excess weight gain, hepatic 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 ceramidase genes Asah2 and Acer3.

• AHR signalling was activated in both gut and liver of offspring perinatally exposed to Ind or I3A
• Trans-repressed target genes included ceramidases Asah2 and Acer3, identified as known and new AHR target genes
• Trans-repression of ceramidases led to increased very long-chain (VLC) ceramides in offspring

Fecal microbiota transfer (FMT) from offspring with perinatal Ind exposure protected naive recipients from WD-induced fibrogenesis and increased beneficial VLC ceramides in recipient livers.

• FMT was performed from perinatally Ind-exposed offspring to naive recipients
• Recipients underwent a 4-week WD challenge following FMT
• FMT protected recipients from WD-induced fibrogenesis
• VLC ceramides were increased in the livers of FMT recipients

In vitro, LX-2 human hepatic stellate cells cultured with Ind or VLC ceramides demonstrated an anti-fibrotic effect that was abolished by AHR inhibition.

• Human LX-2 stellate cells were used to study mechanisms of indole and VLC ceramide effects on TGF-β-induced fibrosis
• Both Ind and VLC ceramides exerted anti-fibrotic effects in LX-2 cells
• The anti-fibrotic effect was abolished when AHR was inhibited, confirming AHR-dependence of the mechanism

Disruptions in early-life gut microbiota and metabolites associated with maternal Western-style diet are linked to MASLD and metabolic diseases in offspring in later life.

• Maternal WD during critical windows of development is associated with metabolic and inflammatory diseases in offspring
• These disruptions can alter microbial metabolite production, including tryptophan derivatives
• Tryptophan derivatives are described as crucial for immune and metabolic regulation
• The specific effects of maternal supplementation with tryptophan metabolites on offspring gut microbiome maturation and MASLD risk were previously unexplored

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.

• The authors describe this as a novel therapeutic pathway for prevention of pediatric MASLD
• The protective mechanism involves the AHR signalling axis linking indole exposure to ceramide metabolism
• Both gut and liver AHR activation were implicated in the sustained protective effects