Maternal high fat diet (MHFD) increased colitis susceptibility in adulthood. However, the mechanism remains unclear. We sought to explore whether novel gut immune receptor leucine-rich repeat C19 (LRRC19) contributed to the impaired mucus barrier of offspring exposed to MHFD via gut immune response and microbiota. The results showed that MHFD significantly impaired the intestinal mucus barrier of offspring, and up-regulated the expression of LRRC19. Lrrc19 deletion alleviated the mucus barrier disruption. Mechanistically, metagenome sequencing revealed that the MHFD-induced gut microbiota alteration was partly restored in Lrrc19