Maternal high-fat diet disrupts intestinal mucus barrier of offspring by regulating gut immune receptor LRRC19

Area of Science:

• Immunology
• Microbiology
• Gastroenterology

Background:

• Maternal high-fat diet (MHFD) increases offspring susceptibility to colitis.
• The underlying mechanisms for MHFD-induced gut dysfunction remain unclear.

Purpose of the Study:

• To investigate the role of the gut immune receptor leucine-rich repeat C19 (LRRC19) in MHFD-induced gut barrier impairment.
• To explore the impact of LRRC19 on gut immune response and microbiota composition in offspring exposed to MHFD.

Main Methods:

• Mice were exposed to MHFD during gestation.
• Intestinal mucus barrier integrity, LRRC19 expression, gut microbiota composition (metagenome sequencing), and targeted metabolomics were analyzed.
• Lrrc19 knockout (Lrrc19^-/-) mice were used to assess the protective effects of LRRC19 deletion.

Main Results:

• MHFD significantly impaired the intestinal mucus barrier and upregulated LRRC19 expression in offspring.
• Lrrc19 deletion alleviated mucus barrier disruption and partially restored MHFD-induced gut microbiota alterations.
• Lrrc19^-/- offspring showed increased Akkermansia muciniphila and Lactobacillus reuteri, a producer of indole-3-acetic acid (IAA).
• IAA improved mucus barrier function by enhancing IL-22⁺ ILC3 cells via the AhR pathway.

Conclusions:

• MHFD disrupts the offspring intestinal mucus barrier by regulating the gut immune receptor LRRC19.
• Imbalances in gut microbiota and metabolites, particularly IAA, play a crucial role in MHFD-induced gut dysfunction.
• Targeting LRRC19 and modulating gut microbiota-derived metabolites like IAA may offer therapeutic strategies against MHFD-related gut issues.