Gut microbiota-derived ursodeoxycholic acid alleviates low birth weight-induced colonic inflammation by enhancing M2 macrophage polarization

Low birth weight (LBW) is associated with intestinal inflammation and dysbiosis after birth. However, the underlying mechanism remains largely unknown. In the present study, we aimed to investigate the metabolism, therapeutic potential, and mechanisms of action of bile acids (BAs) in LBW-induced intestinal inflammation in a piglet model. The fecal microbiome and BA profile between LBW and normal birth weight (NBW) neonatal piglets were compared. Fecal microbiota transplantation (FMT) was employed to further confirm the linkage between microbial BA metabolism and intestinal inflammation. The therapeutic potential of ursodeoxycholic acid (UDCA), a highly differentially abundant BA between LBW and NBW piglets, in alleviating colonic inflammation was evaluated in both LBW piglets, an LBW-FMT mice model, and a DSS-induced colitis mouse model. The underlying cellular and molecular mechanisms by which UDCA suppresses intestinal inflammation were also investigated in both DSS-treated mice and a macrophage cell line. Microbiomes were analyzed by using 16S ribosomal RNA sequencing. Fecal and intestinal BA profiles were measured by using targeted BA metabolomics. Levels of farnesoid X receptor (FXR) were knocked down in J774A.1 cells with small interfering RNAs. We show a significant difference in both the fecal microbiome and BA profiles between LBW and normal birth weight animals in a piglet model. Transplantation of the microbiota of LBW piglets to antibiotic-treated mice leads to intestinal inflammation. Importantly, oral administration of UDCA, a major BA diminished in the intestinal tract of LBW piglets, markedly alleviates intestinal inflammation in LBW piglets, an LBW-FMT mice model, and a mouse model of colitis by inducing M2 macrophage polarization. Mechanistically, UDCA reduces inflammatory cytokine production by engaging BA receptor FXR while suppressing NF-κB activation in macrophages. These findings establish a causal relationship between LBW-associated intestinal abnormalities and dysbiosis, suggesting that restoring intestinal health and postnatal maldevelopment of LBW infants may be achieved by targeting intestinal microbiota and BA metabolism. Video Abstract.