aAtherosclerosis Group, Anzac Research Institute, Concord, New South Wales
bDepartment of Cardiology, Concord Repatriation General Hospital, Sydney, New South Wales, Australia
Correspondence to Leonard Kritharides, Department of Cardiology, Concord Repatriation General Hospital, Sydney, NSW, 2139, Australia. Tel: +61 297675000; e-mail: firstname.lastname@example.org
The intestine has long been known to regulate the uptake of dietary and liver-derived fatty acids, sterols, and phospholipids. Conversely, the reverse cholesterol transport (RCT) pathway, which mediates centripetal movement of cholesterol from peripheral cells to the liver for release into the (relatively passive) small intestine via the bile, was until recently considered the major route for cholesterol excretion. Recent studies challenge the simplicity of these models and emphasize the active role of the intestine in lipid metabolism in health and disease.
Thus, a major nonbiliary route for the excretion of cholesterol into the intestinal lumen, transintestinal cholesterol transport (TICE), has received attention and is the subject of several recent reviews [1,2▪]. Remarkably, such a route had been reported over 80 years ago , but recent studies have reestablished its potential importance. The transporters regulating TICE and the particles delivering cholesterol are still unknown, although it is clear that TICE is independent of ABCG5/G8 (the major known cholesterol export transporters in enterocytes) and of HDL [4▪], and is amenable to upregulation by LXRα agonists. Importantly, TICE provides a bile transporter-independent mechanism of delivering peripheral cholesterol to the intestine for elimination via the feces, diversifying the avenues by which cholesterol clearance could be promoted.
There is overwhelming evidence that gut microbiota play a major role in human health and metabolic disease, and recent studies identify specific roles in lipid metabolism, atherosclerosis, and RCT. Studies using gut microbiota-free mice have indicated that gut flora can modulate adiposity, bone density, and the immune system (for recent reviews see [5▪,6▪]). It has long been understood that gut microbiota contribute to obesity by direct effects on food digestion and energy harvest. However, a recent study shows that low doses of antibiotics in early life can induce adiposity later in life through changes in the gut microbiome [7▪▪]. When weaning mice were exposed to subtherapeutic doses of antibiotics, changes in the microbiome resulted in increased levels of short-chain fatty acids in the gut and alterations in the regulation of hepatic metabolism of lipids and cholesterol, eventually leading to adiposity.
More recent studies also indicate that metabolites of the gut microbiome can directly affect the physiology of other organs and disease processes, including atherosclerosis. Wang et al. showed that the metabolism of phosphatidylcholine by gut flora promotes the development of atherosclerosis by producing the choline metabolite, trimethylamine N-oxide (TMAO). The gut flora can also have favorable effects, as metabolism of the dietary anthocyanin cyanidin-3-O-β-glucoside to protocatechuic acid (PCA) by gut flora promoted cholesterol efflux, RCT and regression of atherosclerosis in mice by inhibiting miRNA-10b and enhancing ABCA1 and ABCG1 transporter activity [9▪▪,10▪]. These studies clearly show that the interaction between diet and microbiota can alter lipid metabolism beyond the intestine.
Recent studies have emphasized that the composition of gut microbiota is diverse and influenced by many factors including maternal transmission, diet, lifestyle, disease, and antibiotic use [5▪,6▪] and is also communicable [11▪]. Studies in both mice and men, which show that direct manipulation of the gut microbiome improves features associated with metabolic syndrome and obesity [12▪▪,13▪▪], indicate that microbiota-based interventions are promising new targets for treating some diseases. Given that contemporary treatments such as bariatric surgery dramatically alter gut microbiota while decreasing the markers of insulin resistance and inflammation , and endotoxemia decreases RCT , unraveling the mechanistic links between microbiota and cholesterol metabolism may provide new therapeutics to improve RCT and combat atherosclerosis.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
1. Van der Velde AE, Brufau G, Groen AK. Transintestinal cholesterol efflux. Curr Opin Lipidol 2010; 21:167–171.
2▪. Temel RE, Brown JM. Biliary and nonbiliary contributions to reverse cholesterol transport. Curr Opin Lipidol 2012; 23:85–90.
3. Sperry WM. Lipid excretion. IV. A study of the relationship of the bile to the fecal lipids with special reference to certain problems of sterol metabolism. J Biol Chem 1927; 71:351–378.
4▪. Vrins CLJ, Ottenhoff R, van den Oever K, et al. Trans-intestinal cholesterol efflux is not mediated through high density lipoprotein. J Lipid Res 2012; 53:2017–2023.
5▪. Nicholson JK, Holmes E, Kinross J, et al. Host–gut microbiota metabolic interactions. Science (New York, NY) 2012; 336:1262–1267.
6▪. Tremaroli V, Bäckhed F. Functional interactions between the gut microbiota and host metabolism. Nature 2012; 489:242–249.
7▪▪. Cho I, Yamanishi S, Cox L, et al. Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature 2012; 488:621–626.
8. Wang Z, Klipfell E, Bennett BJ, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 2011; 472:57–63.
9▪▪. Wang D, Xia M, Yan X, et al. Gut microbiota metabolism of anthocyanin promotes reverse cholesterol transport in mice via repressing miRNA-10b. Circ Res 2012; 111:967–981.
10▪. Wang Y, Zhang Y, Wang X, et al. Supplementation with cyanidin-3-O-β-glucoside protects against hypercholesterolemia-mediated endothelial dysfunction and attenuates atherosclerosis in apolipoprotein E-deficient mice. J Nutr 2012; 142:1033–1037.
11▪. Henao-Mejia J, Elinav E, Jin C, et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 2012; 482:179–185.
12▪▪. Murphy EF, Cotter PD, Hogan A, et al.
Divergent metabolic outcomes arising from targeted manipulation of the gut microbiota in diet-induced obesity. Gut 2012. [Epub ahead of print]
13▪▪. Vrieze A, Van Nood E, Holleman F, et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 2012; 143:913.e917–916.e917.
14. Furet J-P, Kong L-C, Tap J, et al. Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss: links with metabolic and low-grade inflammation markers. Diabetes 2010; 59:3049–3057.
15. McGillicuddy FC, de la Llera-Moya M, Hinkle CC, et al. Inflammation impairs reverse cholesterol transport in vivo. Circulation 2009; 119:1135–1145.
An excellent recent review of transintesinal cholesterol efflux.
Unlike the hepatobiliary RCT pathway, cholesterol exported via the transintestinal route is not dependent on HDL.
An excellent recent review of the relationships between gut microbiota and their hosts.
An excellent recent review of the relationships between gut microbiota and their hosts.
Exposure of weaning mice to subtherapeutic doses of antibiotics caused changes in their microbiome, resulting in increased levels of short-chain fatty acids in the gut and alterations in the regulation of hepatic metabolism of lipids and cholesterol, eventually leading to adiposity.
This study, which shows that a dietary flavonoid is converted by gut microbiota into a circulating metabolite that regulates cellular cholesterol metabolism and RCT, indicates the importance of the microflora in host lipid metabolism and a potential target for therapeutic intervention.
This study also demonstrates the protective effects of the anthocyanin cyanidin-3-O-β-glucoside in hyperlipidemic mice, showing that it induces significant lowering of plasma cholesterol, reduction of hypercholesterolemia-induced endothelial dysfunction, and decreased atherosclerosis.
An imbalance in intestinal microbiota (associated with inflammasome defects) was associated with increased susceptibility to hepatic steatosis, inflammation, and obesity. Co-housing with wild-type control mice conferred these traits to the control mice, suggesting communicability.
Both an antibiotic and a bacteriocin-producing probiotic changed the gut microbiota in diet-induced obese mice, but only antibiotic treatment improved the metabolic abnormalities associated with obesity. This shows that the gut microbiota is a realistic therapeutic target, and also that the specificity of the antimicrobial agent employed is critical.
This study shows that transplantation of healthy microbiota improves insulin signaling in individuals with metabolic syndrome, raising the prospect of targeted manipulation of the gut microbiome as a therapeutic approach to the treatment of some diseases.