High fat diet-induced hyperlipidemia and tissue steatosis in rabbits through modulating ileal microbiota.

High-fat diet (HFD) and overnutrition are important starting factors that may alter intestinal microbiota, lipid metabolism, and systemic inflammation. However, there were few studies on how intestinal microbiota contributes to tissue steatosis and hyperlipidemia. Here, we investigated the effect of lipid metabolism disorder-induced inflammation via toll-like receptor 2 (TLR-2), toll-like receptor 4 (TLR-4), and nuclear factor-κB (NF-κB) pathways at the intestinal level in response to HFD. Twenty 80-day-old male New Zealand White rabbits were randomly divided into the normal diet group (NDG) and the high-fat diet group (HDG) for 80 days. Growth performance, blood biochemical parameters, lipid metabolism, inflammation, degree of tissue steatosis, and intestinal microbial composition were measured. HFD increased the relative abundance of Christensenellaceae_R_7_group, Marvinbryantia, Akkermansia etc., with a reduced relative abundance of Enterorhabdus and Lactobacillus. Moreover, HFD caused steatosis in the liver and abdominal fat and abnormal expression of some genes related to lipid metabolism and tight junction proteins. The TLR-2, TLR-4, NF-κB, TNF-α, and IL-6 were confirmed by overexpression with downregulation of IL-10. Serum biochemical indices (TG, TCHO, LDL-C, and HDL-C) were also increased, indicating evidence for the development of the hyperlipidemia model. Correlation analysis showed that this microbial dysbiosis was correlated with lipid metabolism and inflammation, which were associated with the intestinal tract's barrier function and hyperlipidemia. These results provide an insight into the relationship between HFD, the intestinal microbiota, intestinal barrier, tissue inflammation, lipid metabolism, and hyperlipidemia. KEY POINTS: • High-fat diet leads to ileal microbiota disorders • Ileal microbiota mediates local and systemic lipid metabolism disorders and inflammation • There is a specific link between ileal microbiota, histopathology, and hyperlipidemia.

Dietary Fiber Ameliorates Lipopolysaccharide-Induced Intestinal Barrier Function Damage in Piglets by Modulation of Intestinal Microbiome.

Weaning of piglets is accompanied by intestinal inflammation, impaired intestinal barrier function, and intestinal microflora disorder. Regulating intestinal microflora structure can directly or indirectly affect intestinal health and host growth and development. However, whether dietary fiber (DF) affects the inflammatory response and barrier function by affecting the intestinal microflora and its metabolites is unclear. In this study, we investigated the role of intestinal microflora in relieving immune stress and maintaining homeostasis using piglets with lipopolysaccharide (LPS)-induced intestinal injury as a model. DF improved intestinal morphology and barrier function, inhibited the expression of inflammatory signal pathways (Toll-like receptor 2 [TLR2], TLR4, and NF-κB) and proinflammatory cytokines (interleukin 1ß [IL-1ß], IL-6, and tumor necrosis factor alpha [TNF-α]), and upregulated the expression of barrier-related genes (encoding claudin-1, occludin, and ZO-1). The contents of proinflammatory cytokines (IL-1ß, IL-6, and TNF-α) and the activity of diamine oxidase in plasma were decreased. Meanwhile, DF had a strong effect on the composition and function of intestinal microflora at different taxonomic levels, the relative abundances of cellulolytic bacteria and anti-inflammatory bacteria were increased, and the concentrations of propionate, butyrate, and total short-chain fatty acids (SCFAs) in intestinal contents were increased. In addition, the correlation analysis also revealed the potential relationship between metabolites and certain intestinal microflora, as well as the relationship between metabolites and intestinal morphology, intestinal gene expression, and plasma cytokine levels. These results indicate that DF improves intestinal barrier function, in part, by altering intestinal microbiota composition and increasing the synthesis of SCFAs, which subsequently alleviate local and systemic inflammation.IMPORTANCE Adding DF to the diet of LPS-challenged piglets alleviated intestinal and systemic inflammation, improved intestinal barrier function, and ultimately alleviated the growth retardation of piglets. In addition, the addition of DF significantly increased the relative abundance of SCFA-producing bacteria and the production of SCFAs. We believe that the improvement of growth performance of piglets with LPS-induced injury can be attributed to the beneficial effects of DF on intestinal microflora and SCFAs, which reduced the inflammatory response in piglets, improving intestinal barrier function and enhancing body health. These research results provide a theoretical basis and guidance for the use of specific fiber sources in the diet to improve intestinal health and growth performance of piglets and thus alleviate weaning stress. Our data also provide insights for studying the role of DF in regulating gastrointestinal function in human infants.

S100A4 promotes invasion and angiogenesis in breast cancer MDA-MB-231 cells by upregulating matrix metalloproteinase-13.

S100A4 is a member of the S100 family of calcium-binding proteins that is directly involved in tumor metastasis. In the present study, we examined the potential role of S100A4 in metastasis in breast cancer and its relation with matrix metalloproteinase-13 (MMP-13). Analysis of 100 breast cancer specimens including 50 with and 50 without lymph node metastasis showed a significant upregulation of S100A4 and MMP-13 expression in metastatic breast cancer tissues. Positive immunoreactivity for S100A4 was associated with MMP-13 expression. Overexpression of S100A4 in the MDA-MB-231 breast cancer cell line upregulated MMP13 expression leading to increased cell migration and angiogenesis. SiRNA-mediated silencing of S100A4 downregulated MMP13 expression and suppressed cell migration and angiogenesis. Moreover, neutralization of MMP-13 activity with a specific antibody blocked cell migration and angiogenesis in MDA-MB-231/S100A4 cells. In vivo siRNA silencing of S100A4 significantly inhibited lung metastasis in transgenic mice. The present results suggest that the S100A4 gene may control the invasive potential of human breast cancer cells by modulating MMP-13 levels, thus regulating metastasis and angiogenesis in breast tumors. S100A4 could therefore be of value as a biomarker of breast cancer progression and a novel therapeutic target for human breast cancer treatment.