Low-Density Lipoprotein Receptor Signaling Mediates the Triglyceride-Lowering Action of Akkermansia muciniphila in Genetic-Induced Hyperlipidemia.

OBJECTIVE: Akkermansia muciniphila (A muciniphila) is a mucin-degrading bacterium that resides in the mucus layer whose abundance inversely correlates with body weight and the development of diabetes mellitus in mice and humans. The objective of this study was to explore the regulatory effect of A muciniphila on host lipoprotein metabolism, insulin sensitivity, and hepatic metabolic inflammation. APPROACH AND RESULTS: By establishing a novel mouse model that colonized the A muciniphila in the gastrointestinal tract of the cAMP-responsive binding protein H (CREBH)-deficient mouse and in vivo chylomicron assay, we found that increased colonization of A muciniphila in the gastrointestinal tract of wild-type mice protected mice from an acute fat load-induced hyperlipidemia compared with vehicle-treated mice. A muciniphila administration also significantly ameliorated chronic hypertriglyceridemia, improved insulin sensitivity, and prevented overproduction of postprandial chylomicrons in CREBH-null mice. Mechanistic studies revealed that increased A muciniphila colonization induced expression of low-density lipoprotein receptors and apolipoprotein E in the hepatocytes of CREBH-null mice, which facilitated the uptake of intermediate-density lipoprotein via the mediation of apolipoprotein B100 and apolipoprotein E, leading to the increased clearance of triglyceride-rich lipoprotein remnants, chylomicron remnants, and intermediate-density lipoproteins, from the circulation. Treatment with A muciniphila further improved hepatic endoplasmic reticulum stress and metabolic inflammation in CREBH-null mice. CONCLUSIONS: Increased colonization of the disease-protective gut bacteria A muciniphila protected the host from acute and chronic hyperlipidemia by enhancing the low-density lipoprotein receptor expression and alleviating hepatic endoplasmic reticulum stress and the inflammatory response in CREBH-null mice.

Effects of heat-killed Lactobacillus pentosus S-PT84 on postprandial hypertriacylglycerolemia in rats.

The effect of Lactobacillus pentosus strain S-PT84 (S-PT84) on postprandial hypertriacylglycerolemia was investigated in rats. S-PT84 dose-dependently inhibited the hydrolysis of triacylglycerols by pancreatic lipase in vitro. Intragastric administration of S-PT84 significantly reduced the lymphatic recovery of (3)H-trioleoylglycerol up to 8 h. The oral administration of a fat emulsion, with or without S-PT84, resulted in the concentration of plasma triacylglycerol 2 h and 3 h after administration being significantly lower in the S-PT84 group than in the group without S-PT84 (control group). These results suggest that S-PT84 alleviated postprandial hypertriacylglycerolemia by delaying triacylglycerol absorption in the intestine through the inhibition of pancreatic lipase.

Variations in Gut Microbiome are Associated with Prognosis of Hypertriglyceridemia-Associated Acute Pancreatitis.

Hypertriglyceridemia-associated acute pancreatitis (HTGAP) is linked with increased severity and morbidity. Intestinal flora plays an important role in the progression of acute pancreatitis (AP). However, pathogenetic association between gut microbiota and HTGAP remains unknown. In this study, we enrolled 30 HTGAP patients and 30 patients with AP that is evoked by other causes. The V3-V4 regions of 16S rRNA sequences of the gut microbiota were analyzed. Clinical characteristics, microbial diversity, taxonomic profile, microbiome composition, microbiological phenotype, and functional pathways were compared between the two groups. Our results showed that the HTGAP group had a higher proportion of severe AP (46.7% vs. 20.0%), organ failure (56.7% vs. 30.0%), and a longer hospital stay (18.0 days vs. 6.5 days). HTGAP group also had poorer microbial diversity, higher abundances of Escherichia/Shigella and Enterococcus, but lower abundances of Dorea longicatena, Blautia wexlerae, and Bacteroides ovatus as compared with non-HTGAP group. Correlation analysis revealed that gut bacterial taxonomic and functional changes were linked with local and systemic complications, ICU admission, and mortality. This study revealed that alterations of gut microbiota were associated with disease severity and poor prognosis in HTGAP patients, indicating a potential pathophysiological link between gut microbiota and hypertriglyceridemia related acute pancreatitis.

Diurnal Rhythmicity Programs of Microbiota and Transcriptional Oscillation of Circadian Regulator, NFIL3.

Circadian rhythms are a very exquisite mechanism to influence on transcriptional levels and physiological activities of various molecules that affect cell metabolic pathways. Long-term alteration of circadian rhythms increases the risk of cardiovascular diseases, hypertension, hypertriglyceridemia, and metabolic syndrome. A drastic change in dietary patterns can affect synchronizing the circadian clock within the metabolic system. Therefore, the interaction between the host and the bacterial community colonizing the mammalian gastrointestinal tract has a great impact on the circadian clock in diurnal programs. Here, we propose that the microbiota regulates body composition through the transcriptional oscillation of circadian regulators. The transcriptional regulator, NFIL3 (also called E4BP4) is a good example. Compositional change of the commensal bacteria influences the rhythmic expression of NFIL3 in the epithelium, which subsequently controls obesity and insulin resistance. Therefore, control of circadian regulators would be a promising therapeutic target for metabolic diseases.

Supplementation with two probiotic strains, Lactobacillus curvatus HY7601 and Lactobacillus plantarum KY1032, reduces fasting triglycerides and enhances apolipoprotein A-V levels in non-diabetic subjects with hypertriglyceridemia.

OBJECTIVE: Previous studies have indicated that supplementation with probiotics might improve lipid metabolism. The objective of the study was to evaluate the effect of supplementation with probiotic strains Lactobacillus curvatus (L. curvatus) HY7601 and Lactobacillus plantarum (L. plantarum) KY1032 on triglyceride (TG) and apolipoprotein A-V (apo A-V) levels. METHODS: A randomized, double-blinded, placebo-controlled study was conducted with 128 non-diabetic subjects with hypertriglyceridemia. Over a 12-week test period, the probiotic group consumed 2 g/day of a powdered supplement containing L. curvatus HY7601 and L. plantarum KY1032, whereas the placebo group consumed a powder lacking probiotics. RESULTS: After the treatment, the probiotic group showed an 18.3% (P < 0.001) reduction in TGs and increases of 21.1% (P = 0.001) and 15.6% (P < 0.001) in the apo A-V and LDL particle size, respectively. The probiotic group had a significant reduction in TGs (P = 0.040) and increases in the plasma apo A-V (P = 0.003) and LDL particle size (P < 0.001) compared with the placebo group. In the probiotic group, the reduction in the TG levels was negatively correlated with changes in the apo A-V and baseline TGs, regardless of the APOA5 -1131T > C genotype. CONCLUSION: The consumption of two probiotic strains for 12 weeks reduced TGs and increased the apo A-V and LDL particle size in hypertriglyceridemic subjects. This effect was more pronounced in subjects with higher levels of fasting TGs regardless of their APOA5 -1131T > C genotype.

[Hypocholesterolemia during the acute phase of an inflammatory reaction of infectious origin. 120 cases]. / Hypocholestérolémie au cours de la phase aiguë de la réaction inflammatoire d'origine infectieuse. A propos de 120 cas.

OBJECTIVES: Transitory changes in the plasma levels of lipids, cholesterol and triglycerides have been observed since a long time by many authors, in the course of bacterial infections, with hypocholesterolemia, hypertriglyceridemia in the acute phase, increasing the third day of clinical evolution. Their decrease accompanies the return to normal. Lymphopenia is also observed during bacterial infections and as the very low level of cholesterol, is considered to be a factor of critical prognosis, predicting an unfavorable evolution, essentially in elderly people. C-reactive protein (CRP) proves to be a good marker protein in inflammation due to sepsis; its synthesis is directly influenced by the cytokines released during the acute phase response of inflammation in bacterial infection. The authors are researching a correlation between the intensity of the acute phase response represented by CRP levels, and a reduced cholesterol level, or a hypertriglyceridemia, or lymphocytopenia. METHODS: In this prospective study, blood samples at fasting state were obtained in 160 patients divided into four groups of 40 according to CRP levels, including a witness group (CRP levels lower than 10 mg/L) and three groups of patients presenting infectious diseases with acute phase response of different intensities. All patients were checked for cholesterol, triglyceride and CRP levels, blood cell count. The three pathologic groups were compared to the witness group and to each other. RESULTS: A significant correlation was established between the intensity of the acute phase response during sepsis and reduced levels of cholesterol. Cholesterolemia was reduced (P < 0.05) in all three pathologic groups when compared to the witness group; the difference existed when a low intensity inflammatory response was observed (mean CRP level 27.6 (10.5) mg/L in group 1). Moreover a significant response exists with reduced cholesterol levels between group 4 (mean CRP level 250 (73) mg/L) and group 1. Lymphocytopenia was observed in all three pathologic groups, without evident link with the CRP levels. No modification was observed concerning triglyceride levels. CONCLUSIONS: The authors report a negative correlation of total cholesterol to CRP levels at the early stage of infections diseases. Prior studies established a negative correlation between inflammatory parameters during bacterial infections and total cholesterol and HDL fraction. Considering the plasma lipid pathways, HDL fraction plays a major role in lipid transport and exchanges between lipoproteins, thanks to its apolipoproteins A1, A2 and C. IL-1 and TNF, two cytokines involved in the acute phase response, have metabolic functions which could possibly contribute to reduce plasma total cholesterol and HDL2 fraction. IL-1 also induces lymphocytopenia. The authors propose the hypothesis of a correlation between plasma cholesterol levels and the acute phase response during sepsis, which could be induced by the mediators or effectors of inflammation.