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C. scindens and a small number of species belonging to the genus Clostridium are responsible for significant alterations in the human bile acid pool composition through bile acid 7α/β dehydroxylation

bile acids play an important role in maintaining intestinal barrier function as antimicrobial agents in the small bowel (37, 38) and inducers of antimicrobial peptides

Perturbations in the biliary bile acid pool composition can be indicative of hepatogastrointestinal diseases such as fat malabsorption (40), gallstones (3), gastrointestinal cancers (41), and possibly type II diabetes

modifications of hepatic Cyp8b1 expression and the subsequent alteration of bile acid metabolites

Expression and activity of major drug-metabolizing enzymes (Cyp3a11 and Cyp2c29) were also significantly stimulated

The gut microbiota (GM) exhibits a relatively low level of diversity compared to those of most soil ecosystems and in humans it is comprised of usually no more than nine phyla of microorganisms, of which only two are dominant: the Firmicutes and the Bacteroidetes

colonization of a germfree gut was rapid and remarkably stable, establishing within only a week after first exposure

a study conducted on germfree rats by Nicholls et al. showed that 3 weeks were necessary to obtain a stabilization and “normalization”

the microbiota status affects the systemic metabolism of the host, modulating the metabolic fingerprint of topographically remote organs such as the liver and the kidney

Gut colonization induces a rapid weight gain associated with stimulation of hepatic glycogenesis and triglyceride synthesis

Gut colonization alters bile acid metabolite profiles via modulation of hepatic Cyp8b1 expression

Bile acids are well-known contributors to glucose and lipid metabolism in the liver

GM is known to alter bile metabolism

GM is also known to exert a strong influence on the metabolism of xenobiotics

these classes can be further refined by improved separation procedures, and intermediate-density lipoproteins (IDL) and subdivisions of the HDL (e.g. HDL1, HDL2, HDL3 and so forth

Density is determined largely by the relative concentrations of triacylglycerols and proteins and by the diameters of the broadly spherical particles

Lipoproteins are spherical (VLDL, LDL, HDL) to discoidal (nascent HDL) in shape with a core of non-polar lipids, triacylglycerols and cholesterol esters, and a surface monolayer, ~20Å thick, consisting of apoproteins, phospholipids and non-esterified cholesterol, which serves to present a hydrophobic face to the aqueous phase

the various lipid components should not be considered as absolute, as they are in a state of constant flux

Apo A1 is the main protein component of HDL

Apo A2 is the second most important HDL apolipoprotein

the main groups are classified as chylomicrons (CM), very-low-density lipoproteins (VLDL), low-density lipoproteins (LDL) and high-density lipoproteins (HDL), based on the relative densities of the aggregates on ultracentrifugation

The lipoproteins can be categorised simplistically according to their two main metabolic functions. The principal role of the chylomicrons and VLDL is to transport triacylglycerols ‘forward’ as a source of fatty acids from the intestines or liver to the peripheral tissues. In contrast, the HDL remove excess cholesterol from peripheral tissues and deliver it to the liver for excretion in bile in the form of bile acids (‘reverse cholesterol transport’). While these functions are considered separately here for convenience, it should be recognised that the processes are highly complex and inter-related, and they involve transfer of apoproteins, enzymes and lipid constituents among the heterogeneous mix of all the lipoprotein fractions.

The starting point for innate immunity activation is the recognition of conserved structures of bacteria, viruses, and fungal components through pattern-recognition receptors

TLRs are PRRs that recognize microbe-associated molecular patterns

TLRs are transmembrane proteins containing extracellular domains rich in leucine repeat sequences and a cytosolic domain homologous to the IL1 receptor intracellular domain

The major proinflammatory mediators produced by the TLR4 activation in response to endotoxin (LPS) are TNFα, IL1β and IL6, which are also elevated in obese and insulin-resistant patients

Obesity, high-fat diet, diabetes, and NAFLD are associated with higher gut permeability leading to metabolic endotoxemia.

Probiotics, prebiotics, and antibiotic treatment can reduce LPS absorption

LPS promotes hepatic insulin resistance, hypertriglyceridemia, hepatic triglyceride accumulation, and secretion of pro-inflammatory cytokines promoting the progression of fatty liver disease.

In the endothelium, LPS induces the expression of pro-inflammatory, chemotactic, and adhesion molecules, which promotes atherosclerosis development and progression.

In the adipose tissue, LPS induces adipogenesis, insulin resistance, macrophage infiltration, oxidative stress, and release of pro-inflammatory cytokines and chemokines.

the gut microbiota has been recently proposed to be an environmental factor involved in the control of body weight and energy homeostasis by modulating plasma LPS levels

dietary fats alone might not be sufficient to cause overweight and obesity, suggesting that a bacterially related factor might be responsible for high-fat diet-induced obesity.

This was accompanied in high-fat-fed mice by a change in gut microbiota composition, with reduction in Bifidobacterium and Eubacterium spp.

n humans, it was also shown that meals with high-fat and high-carbohydrate content (fast-food style western diet) were able to decrease bifidobacteria levels and increase intestinal permeability and LPS concentrations

it was demonstrated that, more than the fat amount, its composition was a critical modulator of ME (Laugerette et al. 2012). Very recently, Mani et al. (2013) demonstrated that LPS concentration was increased by a meal rich in saturated fatty acids (SFA), while decreased after a meal rich in n-3 polyunsaturated fatty acids (n-3 PUFA).

this effect seems to be due to the fact that some SFA (e.g., lauric and mystiric acids) are part of the lipid-A component of LPS and also to n-3 PUFA's role on reducing LPS potency when substituting SFA in lipid-A

these experimental results suggest a pivotal role of CD14-mediated TLR4 activation in the development of LPS-mediated nutritional changes.

This suggests a link between gut microbiota, western diet, and obesity and indicates that gut microbiota manipulation can beneficially affect the host's weight and adiposity.

endotoxemia was independently associated with energy intake but not fat intake in a multivariate analysis

in vitro that endotoxemia activates pro-inflammatory cytokine/chemokine production via NFκB and MAPK signaling in preadipocytes and decreased peroxisome proliferator-activated receptor γ activity and insulin responsiveness in adipocytes.

T2DM patients have mean values of LPS that are 76% higher than healthy controls

LPS-induced release of glucagon, GH and cortisol, which inhibit glucose uptake, both peripheral and hepatic

LPSs also seem to induce ROS-mediated apoptosis in pancreatic cells

Recent evidence has been linking ME with dyslipidemia, increased intrahepatic triglycerides, development, and progression of alcoholic and nonalcoholic fatty liver disease

The hepatocytes, rather than hepatic macrophages, are the cells responsible for its clearance, being ultimately excreted in bile

All the subclasses of plasma lipoproteins can bind and neutralize the toxic effects of LPS, both in vitro (Eichbaum et al. 1991) and in vivo (Harris et al. 1990), and this phenomenon seems to be dependent on the number of phospholipids in the lipoprotein surface (Levels et al. 2001). LDL seems to be involved in LPS clearance, but this antiatherogenic effect is outweighed by its proatherogenic features

LPS produces hypertriglyceridemia by several mechanisms, depending on LPS concentration. In animal models, low-dose LPS increases hepatic lipoprotein (such as VLDL) synthesis, whereas high-dose LPS decreases lipoprotein catabolism

When a dose of LPS similar to that observed in ME was infused in humans, a 2.5-fold increase in endothelial lipase was observed, with consequent reduction in total and HDL. This mechanism may explain low HDL levels in ‘ME’ and other inflammatory conditions such as obesity and metabolic syndrome

It is known that the high-fat diet and the ‘ME’ increase intrahepatic triglyceride accumulation, thus synergistically contributing to the development and progression of alcoholic and NAFLD, from the initial stages characterized by intrahepatic triglyceride accumulation up to chronic inflammation (nonalcoholic steatohepatitis), fibrosis, and cirrhosis

On the other hand, LPS activates Kupffer cells leading to an increased production of ROS and pro-inflammatory cytokines like TNFα

high-fat diet mice presented with ME, which positively and significantly correlated with plasminogen activator inhibitor (PAI-1), IL1, TNFα, STAMP2, NADPHox, MCP-1, and F4/80 (a specific marker of mature macrophages) mRNAs

prebiotic administration reduces intestinal permeability to LPS in obese mice and is associated with decreased systemic inflammation when compared with controls

Cani et al. also found that high-fat diet mice presented with not only ME but also higher levels of inflammatory markers, oxidative stress, and macrophage infiltration markers

This suggests that important links between gut microbiota, ME, inflammation, and oxidative stress are implicated in a high-fat diet situation

high-fat feeding is associated with adipose tissue macrophage infiltration (F4/80-positive cells) and increased levels of chemokine MCP-1, suggesting a strong link between ME, proinflammatory status, oxidative stress, and, lately, increased CV risk

LPS has been shown to promote atherosclerosis

markers of systemic inflammation such as circulating bacterial endotoxin were elevated in patients with chronic infections and were strong predictors of increased atherosclerotic risk

As a TLR4 ligand, LPS has been suggested to induce atherosclerosis development and progression, via a TLR4-mediated inflammatory state.

hese genera proliferate, occupy most available niches, and produce metabolic waste products such as acetic, butyric, and lactic acids

Anaerobic bacteria can then deconjugate bile acids in this region and bind available vitamin B12 so that the vitamin and fats are malabsorbed

Distinction between soluble and insoluble dietary fibers is based on the solubility characteristics of dietary fiber in hot aqueous buffer solutions

Insoluble fibers primarily consist of cellulose and some hemicelluloses, resistant starch, and chitin while soluble fibers include pectins, β-glucans, galactomannan gums, mucilages, and some hemicelluloses

insoluble fibers increase fecal bulk and the excretion of bile acids and decrease intestinal transit time

Soluble fibers increase total transit time by delaying gastric emptying and also slow glucose absorption

only soluble viscous fibers delay gastric emptying time and slow glucose absorption while nonviscous soluble fibers primarily act as a substrate for microbial fermentation in the colon