Several factors during pregnancy, such as changes in serotonin (5-HT) levels, can affect intestinal function in offspring mice. The role of 5-HT in regulating intestinal motility after lipopolysaccharide (LPS) exposure during pregnancy is unclear. In this study, Tlr4^fl/fl and Tlr4^▵IEC mice were injected with LPS or phosphate-buffered saline during pregnancy to obtain prenatal LPS-exposed or non-exposed offspring mice. Changes in intestinal morphology, motility, and the TLR4 and 5-HT signaling pathways were examined in male offspring mice. The role of TLR4 in regulating 5-HT secretion was investigated in the BON-1 enterochromaffin cell line. In the prenatal LPS-exposed Tlr4^fl/fl group, offspring mice exhibited colonic mucosal injury and faster intestinal motility, but these effects were absent when TLR4 was knocked out in intestinal epithelial cells. The TLR4 and 5-HT signaling pathways were activated in the colon of prenatal LPS-exposed Tlr4^fl/fl offspring mice but were inactivated in prenatal LPS-exposed Tlr4 knockout offspring mice. In BON-1 cells, TLR4 interacted with the calcium ion channel PIEZO1, causing calcium influx and promoting 5-HT secretion. This process was disrupted by the TLR4 inhibitor TAK242. LPS exposure during pregnancy affected intestinal motility in offspring mice by activating TLR4 pathways in the colon and increasing 5-HT secretion from enterochromaffin cells. The effects of LPS on the intestine might be explained by the interaction between TLR4 and PIEZO1, suggesting that TLR4 is related to abnormal intestinal motility in offspring mice exposed to LPS during pregnancy.

Vitamin A (VA) plays an essential role in modulating both the gut microbiota and gut barrier function. Short-chain fatty acids (SCFAs), as metabolites of the gut microbiota, protect the physiological intestinal barrier; however, they are compromised when VA is deficient. Thus, there is an urgent need to understand how and which SCFAs modulate colonic epithelial barrier integrity in VA deficiency (VAD). Herein, compared with normal VA rats (VAN), at the beginning of pregnancy, we confirmed that the colonic desmosome junction was impaired in the VAD group, and the amounts of acetate, propionate, and butyrate declined because of the decreased abundance of SCFA-producing bacteria (Romboutsia, Collinsella, and Allobaculum). The differentially expressed genes correlated with the gut barrier and the histone deacetylase complex between the VAD and VAN groups were enriched by RNA sequencing. In the VAD group, the expression levels of colonic CEA cell adhesion molecule 1 (CEACAM1) were down-regulated, and the levels of histone deacetylase 1 (HDAC1) and HDAC3 were up-regulated. Intriguingly, the above changes in the VAD groups were rescued by VA supplementation in the early postnatal period. Further study indicated that in Caco-2 cells, butyrate treatment significantly repressed the enrichment of HDAC3 on the promoter of the CEACAM1 gene to induce its expression. Our findings support that butyrate intervention can alleviate the impairment of colonic barrier function caused by VAD, and timely postnatal VA intervention may reverse the damage caused by VAD on gut barrier integrity during pregnancy.