2024-P: Protective Role of Lipocalin 2 in High-Fat Diet-Induced Gut Microbiota Dysbiosis

Abstract

Diet is the most important factor that shapes diversity in gut microbiome. However, what host factors are involved in dietary regulation of gut microbiota remains largely unknown. Lipocalin 2 (Lcn2) is expressed in intestine, and its expression is upregulated during acute intestinal inflammation. Herein, we investigated the role of Lcn2 in shaping gut microbiota during high-fat diet (HFD)-induced obesity. First, we showed that 12 weeks of HFD feeding led to a significant increase in Lcn2 protein levels in ileum and colon, but a decrease in Lcn2 levels in feces of C57BL/6J mice. This suggests that Lcn2 release into the gut lumen decreases following long-term HFD feeding. Second, we revealed a time course of HFD-induced changes in gut microbiota. Feces were collected from wild type (WT) and Lcn2 knockout (LKO) mice at 2, 4, 8 and 16 weeks of HFD feeding for DNA extraction and 16S sequencing. Compared to WT mice, LKO mice displayed a trend towards lower bacterial diversity (p=0.078) at 4 weeks but not 16 weeks of HFD feeding, suggesting that Lcn2 may have a protective role against gut microbiota dysbiosis during short-term HFD consumption. More interestingly, species richness (the number of bacterial species) was increased at 4 and 8 weeks of HFD feeding and then declined 16 weeks after HFD feeding in WT mice; this time-dependent change in the richness was not observed in LKO mice. Principal coordinate analysis indicates a difference in gut microbiota composition between WT and LKO mice when all time points were considered for the analysis. The heatmap shows that the abundance of short-chain fatty acid-producing bacteria such as Lachnospiraceae and Muribaculaceae was significantly decreased in HFD-fed LKO mice. Lastly, upon 16 weeks of HFD feeding, LKO mice had increased levels of STAT3 and NFκB phosphorylation in colon compared to WT mice, suggesting increased intestinal inflammation. We conclude that Lcn2 plays a protective role in HFD-induced intestinal inflammation and gut microbiota dysbiosis. Disclosure X. Qiu: None. M. Macchietto: None. S. Shen: None. X. Chen: None.