Gut microbiome-derived glycine lipids are diet-dependent modulators of hepatic injury and atherosclerosis.

Oral and gut Bacteroidetes produce unique classes of serine-glycine lipodipeptides and glycine aminolipids that signal through host Toll-like receptor 2. These glycine lipids have also been detected in human arteries, but their effects on atherosclerosis are unknown. Here, we sought to investigate the bioactivity of bacterial glycine lipids in mouse models of atherosclerosis. Lipid 654 (L654), a serine-glycine lipodipeptide species, was first tested in a high-fat diet (HFD)-fed Ldlr-/- model of atherosclerosis. Intraperitoneal administration of L654 over 7 weeks to HFD-fed Ldlr-/- mice resulted in hypocholesterolemic effects and significantly attenuated the progression of atherosclerosis. We found that L654 also reduced liver inflammatory and extracellular matrix gene expression, which may be related to inhibition of macrophage activation as demonstrated in vivo by lower major histocompatibility complex class II gene expression and confirmed in cell experiments. In addition, L654 and other bacterial glycine lipids in feces, liver, and serum were markedly reduced alongside changes in Bacteroidetes relative abundance in HFD-fed mice. Finally, we tested the bioactivities of L654 and related lipid 567 in chow-fed Apoe-/- mice, which displayed much higher fecal glycine lipids relative to HFD-fed Ldlr-/- mice. Administration of L654 or lipid 567 for 7 weeks to these mice reduced the liver injury marker alanine aminotransferase, but other effects seen in Ldlr-/- were not observed. Therefore, we conclude that conditions in which gut microbiome-derived glycine lipids are lost, such as HFD, may exacerbate the development of atherosclerosis and liver injury, whereas correction of such depletion may protect from these disorders.

Interplay between diet, the gut microbiome, and atherosclerosis: Role of dysbiosis and microbial metabolites on inflammation and disordered lipid metabolism.

Atherosclerosis remains the leading cause of death worldwide. Lifestyle modification, including diet and exercise, is recommended to be the primary prevention strategy for atherosclerosis. Dietary patterns have been shown to be strongly associated with atherosclerosis risk. In addition, diet-induced modulation of gut microbiota and the resultant microbial metabolites may influence the progression of atherosclerosis. This review summarizes the role of gut dysbiosis and different microbial metabolites in atherosclerosis, and how different diets may promote or prevent atherosclerosis through gut microbiome modulation. Non-digestible carbohydrates can increase the production of microbial metabolite short-chain fatty acids in the gut, protecting the gut barrier and decreasing overall systemic inflammation. High animal protein/L-carnitine diets may contribute to gut microbiome-dependent production of trimethylamine N-oxide, contributing to atherosclerosis by increased foam cell formation, decreased reverse cholesterol transport (RCT), and pro-thrombotic actions. Western/high-fat diets can increase the gut microbiome production of secondary bile acids and influence downstream signaling via farnesoid X receptor and lead to dysbiosis. Dysbiosis leads to the translocation of lipopolysaccharide (LPS) to the bloodstream by compromising the gut barrier. LPS can activate Toll-like receptor 4 signaling and decrease RCT to exacerbate atherosclerosis. Studies showing a relationship between the gut microbiome and atherosclerosis are still mostly through correlation, while causal pathways are still being uncovered. Future research should integrate proteomics and metabolomics to 16S microbiome sequencing to get a complete picture of the pathways, metabolites, and microbes involved, and to elucidate the complex interaction between the gut microbiome and atherosclerosis.

Effects of Milk Polar Lipids on DSS-Induced Colitis Severity Are Dependent on Dietary Fat Content.

In the United States, over three million adults suffer from inflammatory bowel disease (IBD). The gut microbiome, host immune response, and nutrient-microbial interactions are known to play a role in IBD. The relationship between dairy and IBD is controversial; thus, the objectives of this study were to identify how milk polar lipids (MPLs) and anhydrous milk fat affect colitis disease activity, the colonic transcriptome, and the gut microbiome in a mouse model of chemical-induced colitis. Male and female C57BL/6J mice (n = 120) were randomized into either a low (5% w/w) milk fat or a high (21% w/w) milk fat diet supplemented with either 0%, 1%, or 2% w/w of MPLs for three weeks (n = 10/group/sex). Afterwards, colitis was induced using 1% dextran sodium sulfate in drinking water for five days (colitis induction) and then switched to regular water for five days (colitis recovery). Mice fed added MPLs were protected against colitis when fed a high-fat diet, while added MPLs during low-fat diet attenuated disease activity during the colitis induction period yet promoted colitis and inflammation in male mice during the recovery period. Dietary fat content can alter colitis and influence the anti-inflammatory effect of milk polar lipids.

Milk Polar Lipids: Underappreciated Lipids with Emerging Health Benefits.

Milk fat is encased in a polar lipid-containing tri-layer milk fat globule membrane (MFGM), composed of phospholipids (PLs) and sphingolipids (SLs). Milk PLs and SLs comprise about 1% of total milk lipids. The surfactant properties of PLs are important for dairy products; however, dairy products vary considerably in their polar lipid to total lipid content due to the existence of dairy foods with different fat content. Recent basic science and clinical research examining food sources and health effects of milk polar lipids suggest they may beneficially influence dysfunctional lipid metabolism, gut dysbiosis, inflammation, cardiovascular disease, gut health, and neurodevelopment. However, more research is warranted in clinical studies to confirm these effects in humans. Overall, there are a number of potential effects of consuming milk polar lipids, and they should be considered as food matrix factors that may directly confer health benefits and/or impact effects of other dietary lipids, with implications for full-fat vs. reduced-fat dairy.

Cow's milk polar lipids reduce atherogenic lipoprotein cholesterol, modulate gut microbiota and attenuate atherosclerosis development in LDL-receptor knockout mice fed a Western-type diet.

Milk sphingomyelin (SM), a polar lipid (PL) component of milk fat globule membranes, is protective against dyslipidemia. However, it is unclear whether ingestion of milk PLs protect against atherosclerosis. To determine this, male LDLr-/- mice (age 6 weeks) were fed ad libitum either a high-fat, added-cholesterol diet (CTL; 45% kcal from fat, 0.2% cholesterol by weight; n=15) or the same diet supplemented with 1% milk PL (1% MPL; n=15) or 2% milk PL (2% MPL; n=15) added by weight from butter serum. After 14 weeks on diets, mice fed 2% MPL had significantly lower serum cholesterol (-51%) compared to CTL (P<.01), with dose-dependent effects in lowering VLDL- and LDL-cholesterol. Mice fed 2% MPL displayed lower inflammatory markers in the serum, liver, adipose and aorta. Notably, milk PLs reduced atherosclerosis development in both the thoracic aorta and the aortic root, with 2% MPL-fed mice having significantly lower neutral lipid plaque size by 59% (P<.01) and 71% (P<.02) compared to CTL, respectively. Additionally, the 2% MPL-fed mice had greater relative abundance of Bacteroidetes, Actinobacteria and Bifidobacterium, and lower Firmicutes in cecal feces compared to CTL. Milk PL feeding resulted in significantly different microbial communities as demonstrated by altered beta diversity indices. In summary, 2% MPL strongly reduced atherogenic lipoprotein cholesterol, modulated gut microbiota, lowered inflammation and attenuated atherosclerosis development. Thus, milk PL content may be important to consider when choosing dairy products as foods for cardiovascular disease prevention.

Dietary Egg Sphingomyelin Prevents Aortic Root Plaque Accumulation in Apolipoprotein-E Knockout Mice.

Western-style diets have been linked with dyslipidemia and inflammation, two well-known risk factors associated with cardiovascular disease (CVD). Dietary sphingomyelin (SM) has been reported to modulate gut microbiota, and lower serum lipids and inflammation in mice on Western-style diets. However, few studies have examined if nutritionally-relevant intake of dietary SM can impact atherosclerosis progression. Thus, the aim of this study was to determine if incorporating 0.1% (w/w) egg SM (ESM) (equivalent to ~750 mg/day in humans) into a high-fat (45% kcal), cholesterol-enriched diet (HFD) could prevent atheroprogression in apoE-/- mice (n = 15/group). We found that mice fed with the ESM-rich diet had significantly lower epididymal fat mass (-46%) and tended to have higher spleen weights (+15%). There were no significant differences in serum lipids between groups. However, ESM-fed mice had significantly lower alanine aminotransferase (ALT) activity. Additionally, ESM-fed mice displayed significantly less aortic root lipid accumulation (-31%) compared to controls. This improvement in atherosclerosis was paired with over a two-fold reduction in circulating serum amyloid A (SAA) in ESM-fed mice. Finally, there was also a modulation of the gut microbiota with ESM supplementation. ESM may have the potential to prevent atherosclerosis, however further research in the clinical setting is warranted.