Open Access
Issue
OCL
Volume 23, Number 3, May-June 2016
Article Number D306
Number of page(s) 10
Section Dossier: Lipid consumption and functionality: new perspectives / Consommations et fonctionnalités des lipides : nouveaux horizons
DOI https://doi.org/10.1051/ocl/2016009
Published online 25 March 2016

© M.-C. Michalski et al., published by EDP Sciences, 2016

Licence Creative Commons
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1 Introduction

Metabolic diseases such as obesity and type 2 diabetes result from genetic, environmental and nutritional factors. They are characterized by the set up and maintenance of a low-grade inflammatory status, which increases cardiovascular risk (Libby, 2002; Ross, 1999). Low-grade inflammation is revealed by the increased plasma concentration of several mediators including proinflammatory cytokines such as IL-6 and TNF-α, and adipokines as MCP-1, albeit in much lower concentrations than usually observed in a general inflammatory reaction as in septic shock (Blackwell and Christman, 1996). These inflammatory phenomena are currently the focus of numerous researches in nutrition and health because they are strongly involved in the development of obesity-associated metabolic disorders: type 2 diabetes, insulin resistance, atherosclerosis, etc.

However, the origin of metabolic inflammation development remains poorly solved. In altered metabolic state, two types of inflammatory phenomena can occur (Ding and Lund, 2011; Laugerette et al., 2011): chronic metabolic inflammation or so-called “low grade inflammation”, and transient inflammation described in the postprandial phase; or so-called “postprandial inflammation” contributing to maintain the chronic low-grade inflammation.

On a nutritional point of view, the impact of dietary lipids in these phenomena has gained growing interest and results are sometimes conflicting. In healthy, overweight or diabetic subjects, a hypercaloric meal notably with excessive fat content (50 g lipids corresponding to 59.2% of total energy intake (TEI) from sausage, bread, egg, butter and olive oil) increase inflammatory cytokines conversely to a carbohydrate-rich pizza-based meal (Nappo et al., 2002). Moreover, in coronary disease patients, a meal with 65 g of lipids (including soybean-oil based dressing) results in the postprandial increase of plasma IL-6 concentration (Lundman et al., 2007). Moreover in rats, a role of the visceral adipose tissue in postprandial inflammation was shown, notably with an transient increase of the activation of transcription factor NF-κB (Magné et al., 2010).

However, the nutritional mechanisms leading to the development of low-grade inflammation are not fully elucidated. Recent studies show that the intestinal microbiota can be involved. It is now widely known that the composition of intestinal microbiota differs between normal-weight and obese humans, notably with a lower diversity of bacterial species in obesity (Furet et al., 2010; Ley, 2010; Ley et al., 2006; Zhang et al., 2009).

Recent studies revealed that proinflammatory molecules of bacterial origin, naturally present in the intestinal microbiota and thus in the gut, can reach the bloodstream. These are endotoxins (lipopolysaccharides, LPS), whose plasma concentration and/or activity (endotoxemia) is increased in obese people (Libby, 2002), type 2 diabetics (Creely et al., 2007) and patients with Crohn’s disease (Pastor Rojo et al., 2007). Moreover, in ob/ob mice lacking the leptin gene and fed a high-fat diet, antibiotic treatment modifies the gut microbiota and lowers endotoxemia (Cani, Rottier et al., 2008). In humans, consumption of yogurt containing probiotics improved gut barrier and lowered endotoxemia, resulting in decreased metabolic inflammation (Schiffrin et al., 2009). More recently, endotoxemia was reported to be highly correlated with the number of components of the metabolic syndrome (Lassenius et al., 2011).

Altogether, these studies raise the question about the role of dietary lipids in the modulation of metabolic inflammation via intestinal microbiota and the role of endotoxin passage in plasma, which is the topic of this review.

thumbnail Fig. 1

Pro-inflammatory events induced by plasma lipopolysaccharides (LPS). Adapted from Laugerette et al. (2011); Vors et al. (2014). If reaching the bloodstream, LPS are taken up by a specific transport glycoprotein, the lipopolysaccharide-binding protein (LBP), towards immune cells (such as macrophages). Immune cell activation requires a specific molecular complex consisting of the membrane form of the cluster of differentiation 14 (mCD14), the Toll-Like Receptor 4 (TLR4) and the Myeloid Differentiation protein-2 (MD2). The mCD14 is a glycoprotein able to bind the LPS-LBP complex, which can then fix on the TLR4 receptor and the co-receptor MD2 and then mediate signal transduction via the activation of NF-κB (Nuclear Factor-κB). This signalization cascade results in the secretion of proinflammatory cytokines (IL-6, TNF-α, IL-1β, etc.).

2 Endotoxins are proinflammatory molecules

Endotoxins (LPS) constitute 80% of Gram negative bacteria cell wall. Their structure contain a polysaccharide part, the O-specific chain (so-called antigen O) and a lipid part, the lipid A, which is a highly conserved region representing the toxic part of LPS (Osborn et al., 1964). Bacterial LPS are inflammatory molecules, i.e., induce proinflammatory signaling pathways (Fig. 1). Endotoxemia is measured as the endotoxin activity using the Limulus Amoebocyte Lysate test, validated by the European Pharmacopea. It is increasingly used in metabolic studies and therefore was adapted to the plasma of different species to this aim (Laugerette et al., 2015). Of note, emerging methods aim at quantifying LPS molecules via the analysis of 3-hydroxymuristic acid from their lipid A in plasma (Pais de Barros et al., 2015).

If reaching the bloodstream, LPS are taken up by a specific transport protein: the lipopolysaccharide-binding protein (LBP, 60 kDa), secreted mostly by the liver but also by the white adipose tissue (Moreno-Navarrete et al., 2013) and present in plasma at concentrations in the range of 2–20μg/ml (usually ~18 μg/ml in humans) (Gallay et al., 1994). LPS are then transferred to the CD14 receptor (cluster of differentiation 14; Fig. 1), which exists in 2 forms: a membrane form (mCD14) expressed at the membrane of numerous cells (notably macrophages, monocytes etc.) (Hailman et al., 1994), and a soluble form expressed by cells lacking mCD14 such as endothelial cells (Bazil and Strominger, 1991). LBP and sCD14 are considered as markers of endotoxin exposure in plasma (Hiki et al., 1999), because their half-lives (24–48 h) are longer than that of LPS (<8 min in mice and up to 3 h in humans) (Matsushita et al., 2010; Pastor Rojo et al., 2007). Moreover, the ratio LBP/sCD14 is increased in some inflammatory diseases such as Crohn’s disease (Lakatos et al., 2011). On a metabolic standpoint, both forms of CD14 are able to bind the LPS-LBP complex, which can then fix on the TLR4 receptor (toll-like receptor 4) and the co-receptor MD2 (myeloid differenciation protein-2) and then mediate signal transduction via the activation of NF-κB (Nuclear Factor-κB). This signalization cascade results in the secretion of proinflammatory cytokines (IL-6, TNF-α, IL-1β, etc.) (Fig. 1).

Notably, during a septic shock, LBP can transfer LPS to plasma lipoproteins (HDL, chylomicrons), which allows to neutralize endotoxin activity (Eichbaum et al., 1991; Harris et al., 1993; Vreugdenhil et al., 2003). This neutralization results from the link of lipoproteins to their receptors notably in the liver, inducing LPS clearance with bile secretion (Eichbaum et al., 1991; Harris et al., 1993, 1998; Vreugdenhil et al., 2003). Not only LBP but also the phospholipid transfer protein (PLTP) can bind LPS and contribute to detoxification during septic shocks (Gautier et al., 2008).

3 Links between endotoxemia and metabolic diseases

In the context of unbalanced hypercaloric diets, LPS naturally present in the gut can induce metabolic endotoxemia in the long term, thereby actively participating in maintaining metabolic inflammation related to obesity (Kelly et al., 2012; Kemp, 2013). Indeed, pioneering mice studies revealed that the gut microbiota acts as a “tank” of endotoxins that can increase in plasma after a fat-rich meal and induce inflammation (Cani et al., 2007). This so-called “metabolic endotoxemia”, conversely to the usual septic shock endotoxemia, was closely related to changes in the composition of gut microbiota (Cani, Bibiloni et al., 2008). The proof-of-concept studies showed that 4 weeks of lard-based high fat diet in mice (72% of TEI) increases endotoxemia unlike the control chow diet. Endotoxemia induced by this high fat diet was increased 2.7-fold (Cani, Amar et al., 2007). Moreover, chronic infusion of low amounts of LPS, similar to those observed after the high fat diet, in chow-fed mice led to increased weight gain and insulin resistance. However, CD14-KO mice did not develop weight gain and insulin resistance when fed the high fat diet (Cani et al., 2007). Moreover, the increase of endotoxemia was lower (1.4-fold compared with chow-fed mice) when mice were fed a moderate high fat diet with 40% of total energy intake (TEI) as lipids instead of 72% (Cani et al., 2007).

Some reports highlight that increased endotoxin absorption can be triggered by an increase of intestinal permeability (Cani, Bibiloni et al., 2008; de La Serre et al., 2010). Among factors involved in increased intestinal permeability are reported (i) an altered composition of the gut microbiota (Cani and Delzenne, 2010), notably a dysbiosis characterized with decreased bacterial diversity (Le Chatelier, 2013), and (ii) the chronic consumption of lipid-rich palatable foods (Frazier et al., 2011). Both factors are observed in obesity, which could explain the greater intestinal permeability in obese rodents as well as a higher fasting metabolic endotoxemia.

Links have also been described between endotoxemia, lipid metabolism and weight gain. In humans, recent studies showed that plasma endotoxemia was higher in obese subjects with type 2 diabetes (Creely et al., 2007) and in patients suffering from inflammatory gut diseases (Pastor Rojo et al., 2007) compared with healthy controls. Increased intestinal permeability is also associated with visceral adiposity in otherwise healthy women (normal-weight and overweight) (Gummesson et al., 2011). Moreover, increased plasma endotoxemia was associated with higher food intake and correlated notably with higher fat intake in healthy subjects with metabolic and cardiovascular risk factors (Amar et al., 2008). More recently, endotoxin activity was highly correlated with the different components of metabolic syndrome (Lassenius et al., 2011).

4 Intestinal lipid absorption contributes to the translocation of endotoxins in the bloodstream

The postprandial phase has recently been shown to contribute to metabolic endotoxemia due to the co-absorption of LPS with dietary lipids. In fact endotoxins present in the gut due to the lysis of Gram negative bacteria may reach the bloodstream in the postprandial phase by different means: (i) by absorption by the intestinal mucosa during lipid absorption (Cani et al., 2007; Erridge et al., 2007; Ghanim et al., 2009; Laugerette et al., 2011, 2012) (transcellular passage, shown in humans, in rodents and in vitro), (ii) by passive diffusion due to increased intestinal permeability (paracellular passage, shown in rodents) (Cani, Bibiloni et al., 2008), (iii) by bacterial translocation from the gut through intestinal mucosa to peripheral organs (Neal et al., 2006) (shown in vitro and in rodents).

thumbnail Fig. 2

Postprandial endotoxemia and associated inflammation induced by the intestinal transcellular passage of bacterial LPS during lipid absorption (adapted from Vors et al., 2014). During a massive influx of dietary fatty acids in the postprandial phase, the LPS originated from the small intestine can be absorbed thanks to a transcellular passage during the intestinal absorption of dietary lipids. LPS are then transported in the bloodstream thanks to chylomicrons secreted in the postprandial phase. The circulating LPS are then partially taken up by specific transport proteins as described in Figure 1, therefore generating inflammatory events in the vascular endothelium and peripheral tissues.

Table 1

Effect of test meal composition on postprandial endotoxemia in human studies. Adapted from Vors et al. (2014).

Even if it was the most recently described, the phenomenon of postprandial endotoxemia has already been shown in several studies in humans. Table 1 reports the composition of tested meals and major conclusions of these studies (Vors et al., 2014). A first human study revealed that in lean to obese subjects, occasional smokers, a meal containing toasts with 50 g of butter (41 g of fat) was sufficient to transiently induce endotoxemia 30 min after meal ingestion (Erridge et al., 2007). The mechanism of co-absorption lipids/endotoxins consists in a facilitated transport of LPS by chylomicrons secreted in plasma during lipid digestion (Ghoshal et al., 2009; Laugerette et al., 2011) (Fig. 2). In mice 90 min after gavage with a bolus of triolein, plasma endotoxemia increased, conversely to a gavage with tributyrin, a short-chain triglyceride that do not induce chylomicron secretion, or after a chemical product that blunts chylomicron secretion (Ghoshal et al., 2009). Moreover, different studies in healthy and lean humans showed an increase of plasma LPS in the postprandial phase after ingestion of fat-rich meals, with or without carbohydrates (Deopurkar et al., 2010; Ghanim et al., 2010) (Tab. 1). More recently, we showed that the digestion of a mixed meal containing 33 g of lipids from different sources (margarine, butter, olive oil) by healthy non-smoking normal to overweight men, induced a transient increase of postprandial endotoxemia and sCD14 (Fig. 3). This was followed by a peak of proinflammatory cytokine IL-6 at 2 h after the meal (Laugerette et al., 2011). Importantly, isocaloric loads of glucose or orange juice, or water, do not induce postprandial endotoxemia (Deopurkar et al., 2010). Moreover, electronic microscopy and LAL analyses revealed that LPS were partly transported by chylomicrons (Laugerette et al., 2011). Interestingly, 8 weeks of overfeeding (+760 kcal/day as butter, almonds and Emmental cheese) in this cohort resulted in enhancing the postprandial endotoxemia 1.6-fold (Laugerette et al., 2014). Mixed hyperlipidic/hyperglucidic meals (51 g lipids, 81 g carbohydrates) also increase plasma LPS in the postprandial phase in healthy lean men (Ghanim et al., 2009, 2010). Recent studies confirm these results of postprandial endotoxemia in type 2 diabetic subjects consuming 75 g of lipids (Harte et al., 2012) and in morbidly obese subjects consuming a 50 g lipid load (Clemente-Postigo et al., 2012). Among postprandial studies, some used dairy fat (butter or cream), other used mixed fat-rich foods (often eggs and sausage) or simple oil load or, in the form of single food or into mixed meals, and altogether fat intake was high (Tab. 1). Most recently, we showed that increasing fat amount from 10 g to 40 g in a realistic mixed meal (milkfat, bread and skimmed milk) resulted in similar cumulative postprandial endotoxemia in normal-weight healthy men. In contrast, the 40 g-fat meal resulted in a higher cumulative postprandial endotoxemia than the 10 g-fat meal in healthy obese men, associated with an enhanced enrichment of chylomicrons with LPS along the postprandial phase compared to normal-weight subjects (Vors et al., 2015). Therefore, postprandial endotoxemia is modulated by ingested fat amount in obese men, partly through a different LPS handling in plasma by chylomicrons (Fig. 3).

thumbnail Fig. 3

Summary of recent studies about postprandial endotoxemia in lean, overweight or obese men (Laugerette et al., 2011, 2014; Vors et al., 2015). Upper panel: lean to overweight subjects were submitted to the same postprandial test before and after 8 weeks of overfeeding. Lower panel: lean and obese subjects were submitted to two different postprandial tests varying by the amount of fat in the meal.

Altogether, unbalanced diets notably rich in lipids result in increased endotoxemia, notably via the repeated postprandial phases, which can contribute to the development of low-grade inflammation. However, dietary lipids are various in chemical nature and physico-chemical organizations in foods: different fats and oils exist, and each one can be formulated as bulk or more or less emulsified structures, with the use of different emulsifying agents such as proteins or phospholipids (Fig. 4). The impact of these varieties of lipid structures on lipid absorption and endotoxemia is an emerging research field (Bourlieu and Michalski, 2015; Michalski et al., 2013).

thumbnail Fig. 4

Examples of supramolecular organization of lipid molecules in food products, oil-in-water emulsions and emulsifiers, which can impact on digestive and postprandial events. Adapted from Michalski et al. (2013).

thumbnail Fig. 5

Summary of recent studies about the impact of oil composition, emulsified structure and the type of phospholipid emulsifier on endotoxemia and inflammation (Laugerette et al., 2011, 2012; Lecomte et al., 2016). (A) Catheterized rats were forced fed with saline, sunflower oil + saline or an emulsion of sunflower oil in saline using soybean phospholipids (lecithin) as emulsifier and blood was drawn along the postprandial phase. (B) Mice were fed with high-fat diets varying in fat source during 8 weeks and different markers of endotoxemia and inflammation were measured in plasma and adipose tissue. (C) Mice were fed with a synthetic high-fat diet based on palm oil during 8 weeks, or with a modified diet in which 1.2% of the triglycerides have been replace with 1.2% of polar lipids (PL, mainly phospholipids) from either milk or soybean. PC: phosphatidylcholine, PE: phosphatidylethanolamine, PI: phosphatidylinositol, SM: sphingomyelin.

5 Oil composition, emulsified structure and dietary emulsifiers can modulate endotoxemia and associated inflammation

Several studies showed that metabolic endotoxemia can result from intestinal absorption of LPS due to a high fat meal, however, nothing was known until recently about the impact of fats and oils composition on endotoxemia. Moreover, most rodent studies used synthetic diets characterized by a % of TEI as fat greater than 60% and mostly based on lard and devoid of carbohydrates (Cani et al., 2007). Therefore, we designed a study to compare the impact of different oils on long-term markers of endotoxemia and associated metabolic inflammation. Mice were fed during 8 weeks with 4 different high fat diets enriched with either milk fat, refined non-hydrogenated palm oil, rapeseed oil or sunflower oil. Energy intake as fat was similar to occidental diets, namely ~38% (i.e. ~20 wt% in the diet); oils were incorporated in mice chow diet that is mostly based on cereals and soy and fish proteins. Altogether, the palm oil diet resulted in the greatest inflammatory outcome associated with higher LPS transporter LBP, while the rapeseed oil diet resulted in lower inflammation and LBP (Laugerette et al., 2012). We showed that mice fed the palm oil diet presented the highest plasma IL-6 concentration with an increased expression of pro-inflammatory cytokine IL-1β and of LPS receptors TLR4 and CD14 in the white adipose tissue (Laugerette et al., 2012). This increased inflammation in the palm group was also associated with an increased proportion of E. coli (Gram negative bacteria thus containing LPS) in the gut microbiota. In contrast in the white adipose tissue of the group fed with the rapeseed oil diet, a lower expression of inflammation markers and LPS receptors was observed. Our study shows that the lipid composition of the diet can differently modulate the inflammatory outcome related to endotoxin metabolization. Recent acute studies show that this can be partly explained by differences in postprandial endotoxemia according to oil composition. Pigs were fed a meal dough enriched with 50 g of different oils: the lowest cumulative postprandial endotoxemia was measured after fish oil and the highest after coconut oil; while intermediate endotoxemia was observed after a vegetable oil (unspecified containing 50% arachidonic acid, 32% oleic acid and 13% palmitic acid) (Mani et al., 2013). This difference could be explained by the apparent intestinal permeability to LPS, measured on ileon ex-vivo in Ussing chambers using FITC-LPS, which was highest in the coconut oil group and lowest in the fish oil group (Mani et al., 2013). Altogether, oil composition can modify acute and long-term endotoxemia in different animal models, which would now deserve to be confirmed in human studies.

In everyday meals, each oil can be consumed in bulk form or as a fine emulsion. In the rat, we revealed that gavage with an emulsion of sunflower oil using soybean lecithin increased postprandial endotoxemia compared with gavage with the unemulsified sunflower oil (Fig. 5). Moreover, postprandial endotoxin accumulation was positively correlated with that of plasma triglycerides after these different products (Laugerette et al., 2011). In the long term, we explored the impact of different lipid emulsifiers in the diet on metabolic inflammation. Mice were fed a high-fat diet containing 20% of lipids (mostly palm oil) or modified diets in which 1.2% of oil has been replaced with 1.2% soybean phospholipids or 1.2% milk phospholipids. The diet containing soybean PL (commonly called soybean lecithin) induced adipose tissue hypertrophy and increased markers of inflammation, including circulating LBP concentration and its expression by the adipose tissue, compared with the high fat diet devoid of PL (Lecomte et al., 2016). Interestingly, milk PL did not induce such effect, which could be partly due to their effect on providing faster triglyceride digestion and absorption compared with soybean PL as also observed in vitro and in mice (Lecomte et al., 2015). Another mechanism can be due to the differential impact of lipids on goblet cells which secrete the mucus layer in the colon (Fig. 5). Unlike soybean PL, milk PL in the high fat diet were found to increase the number of colonic goblet cells, thereby possibly contributing to an improved gut barrier that can prevent LPS translocation from the colon to the circulation (Lecomte et al., 2016). Consequences in the field of infant nutrition regarding the metabolic impact of native breastmilk fat globules vs artificially formulated fat droplets would deserve to be elucidated (Bourlieu and Michalski, 2015; Gallier et al., 2015).

6 Importance of LPS transporters and receptors regarding the inflammatory outcome of endotoxemia

LPS handled by chylomicrons during the postprandial phase would be rapidly taken up by the LBP that is the acute phase protein transporting LPS in plasma (van Dielen et al., 2001). In healthy metabolic status or in obesity with low-grade inflammation, low plasma LBP concentrations are known to increase the pro-inflammatory activity of LPS (Lamping et al., 1998). In fact, bacterial LPS induce a higher inflammatory response when they are bound to LBP (Mathison et al., 1992; Tobias et al., 1992) and are strong inducers of proinflammatory cytokine secretion (Marshall, 2005) (Fig. 1). Therefore, interest is currently growing about LBP in the context of metabolic endotoxemia studies. In our study in mice showing that a palm oil diet results in metabolic inflammation, plasma IL-6 was highly correlated with plasma LBP concentration in the palm oil group (Laugerette et al., 2012). In lean to obese men, postprandial IL-6 accumulation after meals containing 10 g or 40 g fat was also correlated to plasma LBP concentration (Vors et al., 2015). Moreover regarding the impact of PL emulsifiers, including soybean PL into the high fat diet resulted in higher expression of inflammatory markers in adipose tissue, namely leptin, TNF-alpha and MCP-1, together with a higher expression of LBP. In contrast, milk PL did not induce adipose tissue hypertrophy and inflammation, and both plasma LBP concentration and LBP expression in adipose tissue were lower in this group (Lecomte et al., 2016).

Parallel to LBP, another endotoxin transporter is described, namely sCD14, but the transport of LPS via sCD14 would lead to a different metabolic impact. Interestingly, sCD14 was recently revealed to potentially present beneficial metabolic effects in the context of inflammation-driven insulin resistance (Fernandez-Real et al., 2011). Indeed, LPS handling by sCD14 was previously reported to inhibit LPS activity by orienting them toward detoxification pathway via HDL (Sussman, 2002; Wurfel et al., 1994), thereby exerting anti-inflammatory effects. Such mechanisms of LPS transport and inflammatory outcome were long known in the etiology of sepsis, however their implication in the context of metabolic endotoxemia and inflammation, obesity and type 2 diabetes is recent. Importantly, a dual role of sCD14 was recently revealed in humans. In non-obese humans with low sCD14 plasma concentrations, circulating sCD14 concentrations were positively associated with percent body fat, waist circumference and white blood cell count and negatively associated with insulin sensitivity, revealing a compensatory role (de Courten et al., 2016). In contrast in morbidly obese participants, circulating sCD14 were positively associated with insulin sensitivity, revealing a buffering effect (de Courten et al., 2016). Authors therefore speculate that, once morbid obesity develops, the capacity of maintaining sCD14 synthesis would determine the metabolic impact of endotoxemia.

Our previous mice and human studies are consistent with such proposed role of sCD14. Inflammation in mice fed a palm oil diet was highly correlated with the relative proportion of circulating transporters of LPS (Laugerette et al., 2012). The LBP/sCD14 ratio was higher in this group while mice fed the rapeseed-oil diet presented a lower LBP/sCD14, notably due to a higher sCD14 plasma concentration, resulting in a lower metabolic inflammation (Fig. 5). Therefore, our results suggest that a diet enriched with 20% refined palm oil can result in a more active and pro-inflammatory transport of LPS towards target tissues via a high plasma concentration of LBP and a lower concentration of sCD14. Conversely, a diet enriched with 20% rapeseed oil results in a lower inflammation both in the circulation and in the adipose tissue, notably via an increase of plasma sCD14 concentration (Laugerette et al., 2012). Consistently in lean to overweight men overfed during 8 weeks, increased inflammatory response was associated with increased LBP/sCD14 ratio in plasma (Laugerette et al., 2014) (Fig. 3).

7 Conclusion and future prospects

The relationship between obesogenic diets and endotoxemia is a new concept that contributes to explain the set up and development of low-grade inflammation. Several studies including ours support the concept that the digestion of a meal containing lipids increase the absorption of endotoxins naturally present in the gut, whose metabolic fate will subsequently depend on their handling by different types of transporters in plasma. The long-term consequences of postprandial endotoxemia, occurring repeatedly meal after meal, should now be more deeply elucidated, notably according to lipid composition in the diet. Of note, metabolic disorders themselves can induce and maintain inflammatory processes, which can then prevail on the amount and composition of ingested lipids. With an aim of preventive nutrition strategy, clinical data should thus be interpreted with care, and stigmatization of specific dietary fat sources should be avoided. Diets or meals tested in clinical trials are often unbalanced, notably with excessive fat amounts. Deleterious effects of lipids are then reported but such diets are also characterized by very low fiber content and high carbohydrate content. Therefore in the etiology of metabolic disorders associated with endotoxemia and inflammation, the study of postprandial phenomena should be performed using more equilibrated and realistic meals and diets. This is particularly consistent regarding lipids because they can be provided through a great variety of compositions and structures, in a wide range of food products. Our works allow to foresee that by modulating the amount, composition and/or structure of dietary lipids, notably in emulsions, nutritional strategies can be proposed to limit postprandial endotoxemia and/or to lower the metabolic impact of postprandial endotoxemia and contribute to prevent low-grade inflammation associated with metabolic diseases.

Conflict of interests

M-C Michalski received research funding from the Centre National Interprofessionnel de l’Economie Laitière (CNIEL, French Dairy Interbranch Organization), Nutricia Research, and Sodiaal-Candia R&D and has consultancy activities for food and dairy companies. These activities have no link with the present article. Other authors have no conflict of interest to disclose.

Acknowledgments

We warmfully acknowledge our colleagues of CarMeN laboratory, CRNH Rhône-Alpes and partner laboratories who were contributors and/or coauthors of our publications reported in this review. Cécile Vors thanks INRA and Centre National Interprofessionnel de l’Economie Laitière (CNIEL) for funding her PhD. CV received a Research Prize from Foundation Nestlé France. Manon Lecomte acknowledges funding of PhD thesis from Région Rhône-Alpes ARC1. Fabienne Laugerette acknowledges funding by Institut Carnot LISA and SFD. The funding bodies had no role in study design, data analysis nor decision to publish.

References

  • Amar J, Burcelin R, et al. 2008. Energy intake is associated with endotoxemia in apparently healthy men. Am. J. Clin. Nutr. 87: 1219–1223. [CrossRef] [PubMed] [Google Scholar]
  • Bazil V, Strominger JL. 1991. Shedding as a mechanism of down-modulation of CD14 on stimulated human monocytes. J. Immunol. 147: 1567–1574. [PubMed] [Google Scholar]
  • Blackwell TS, Christman JW. 1996. Sepsis and cytokines: current status. British J. Anaesthesia 77: 110–117. [CrossRef] [Google Scholar]
  • Bourlieu C, Michalski MC. 2015. Structure-function relationship of the milk fat globule. Curr. Opin. Clin. Nutr. Metab. Care 18: 118–127. [CrossRef] [PubMed] [Google Scholar]
  • Cani PD, Delzenne NM. 2010. Impact du microbiote intestinal sur la perméabilité intestinale et les désordres métaboliques liés à l’obésité. Louvain Med. 129: S8–10. [Google Scholar]
  • Cani PD, Amar J, et al. 2007. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56: 1761–1772. [CrossRef] [PubMed] [Google Scholar]
  • Cani PD, Bibiloni R, et al. 2008. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57: 1470–1481. [CrossRef] [PubMed] [Google Scholar]
  • Cani PD, Rottier O, et al. 2008. Changes in gut microbiota control intestinal permeability-induced inflammation in obese and diabetic mice through unexpected dependent mechanisms. Diabetologia 51: S34–S35. [Google Scholar]
  • Clemente-Postigo M, Queipo-Ortuno MI, et al. 2012. Endotoxin increase after fat overload is related to postprandial hypertriglyceridemia in morbidly obese patients. J. Lipid Res. 53: 973–978. [CrossRef] [PubMed] [Google Scholar]
  • Creely SJ, McTernan PG, et al. 2007. Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 292: E740–E747. [CrossRef] [PubMed] [Google Scholar]
  • De Courten B, Moreno-Navarrete JM, et al. 2016. Contrasting association of circulating sCD14 with insulin sensitivity in non-obese and morbidly obese subjects. Mol. Nutr. Food Res. 60: 103–109. [CrossRef] [PubMed] [Google Scholar]
  • De La Serre CB, Ellis CL, et al. 2010. Propensity to high-fat diet-induced obesity in rats is associated with changes in the gut microbiota and gut inflammation. Am. J. Physiol. Gastrointest. Liver Physiol. 299: G440–448. [CrossRef] [PubMed] [Google Scholar]
  • Deopurkar R, Ghanim H, et al. 2010. Differential effects of cream, glucose, and orange juice on inflammation, endotoxin, and the expression of Toll-like receptor-4 and suppressor of cytokine signaling-3. Diabetes Care 33: 991–997. [CrossRef] [PubMed] [Google Scholar]
  • Ding S, Lund PK. 2011. Role of intestinal inflammation as an early event in obesity and insulin resistance. Curr. Opin. Clin. Nutr. Metab. Care 14: 328–333. [CrossRef] [PubMed] [Google Scholar]
  • Eichbaum EB, Harris HW, et al. 1991. Chylomicrons can inhibit endotoxin activity in vitro. J. Surg. Res. 51: 413–416. [CrossRef] [PubMed] [Google Scholar]
  • Erridge C, Attina T, et al. 2007. A high-fat meal induces low-grade endotoxemia: evidence of a novel mechanism of postprandial inflammation. Am. J. Clin. Nutr. 86: 1286–1292. [CrossRef] [PubMed] [Google Scholar]
  • Fernandez-Real JM, Perez del Pulgar S, et al. 2011. CD14 modulates inflammation-driven insulin resistance. Diabetes 60: 2179–2186. [CrossRef] [PubMed] [Google Scholar]
  • Frazier TH, DiBaise JK, et al. 2011. Gut microbiota, intestinal permeability, obesity-induced inflammation, and liver injury. J. Parent. Enteral Nutr. 35: 14S–20S. [CrossRef] [Google Scholar]
  • Furet J-P, Kong L-C, et al. 2010. Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss: links with metabolic and low-grade inflammation markers. Diabetes 59: 3049–3057. [CrossRef] [PubMed] [Google Scholar]
  • Gallay P, Barras C, et al. 1994. Lipopolysaccharide (LPS)-binding protein in human serum determines the tumor necrosis factor response of monocytes to LPS. J. Infect. Dis. 170: 1319–1322. [CrossRef] [PubMed] [Google Scholar]
  • Gallier S, Vocking K, et al. 2015. A novel infant milk formula concept: Mimicking the human milk fat globule structure. Colloids Surf. B 136: 329–339. [CrossRef] [PubMed] [Google Scholar]
  • Gautier T, Klein A, et al. 2008. Effect of plasma phospholipid transfer protein deficiency on lethal endotoxemia in mice. J. Biol. Chem. 283: 18702–18710. [CrossRef] [PubMed] [Google Scholar]
  • Ghanim H, Abuaysheh S, et al. 2009. Increase in plasma endotoxin concentrations and the expression of Toll-like receptors and suppressor of cytokine signaling-3 in mononuclear cells after a high-fat, high-carbohydrate meal: implications for insulin resistance. Diabetes Care 32: 2281–2287. [CrossRef] [PubMed] [Google Scholar]
  • Ghanim H, Sia CL, et al. 2010. Orange juice neutralizes the proinflammatory effect of a high-fat, high-carbohydrate meal and prevents endotoxin increase and Toll-like receptor expression. Am. J. Clin. Nutr. 91: 940–949. [CrossRef] [PubMed] [Google Scholar]
  • Ghoshal S, Witta J, et al. 2009. Chylomicrons promote intestinal absorption of lipopolysaccharides. J. Lipid Res. 50: 90–97. [CrossRef] [PubMed] [Google Scholar]
  • Gummesson A, Carlsson LM, et al. 2011. Intestinal permeability is associated with visceral adiposity in healthy women. Obesity (Silver Spring) 19: 2280–2282. [CrossRef] [PubMed] [Google Scholar]
  • Hailman E, Lichenstein HS, et al. 1994. Lipopolysaccharide (LPS)-binding protein accelerates the binding of LPS to CD14. J. Exp. Med. 179: 269–277. [CrossRef] [PubMed] [Google Scholar]
  • Harris HW, Grunfeld C, et al. 1993. Chylomicrons alter the fate of endotoxin, decreasing tumor necrosis factor release and preventing death. J. Clin. Invest. 91: 1028–1034. [CrossRef] [PubMed] [Google Scholar]
  • Harris HW, Rockey DC, et al. 1998. Chylomicrons alter the hepatic distribution and cellular response to endotoxin in rats. Hepatology 27: 1341–1348. [CrossRef] [PubMed] [Google Scholar]
  • Harte AL, Varma MC, et al. 2012. High fat intake leads to acute postprandial exposure to circulating endotoxin in type 2 diabetic subjects. Diabetes Care 35: 375–382. [CrossRef] [PubMed] [Google Scholar]
  • Hiki N, Berger D, et al. 1999. Changes in endotoxin-binding proteins during major elective surgery: Important role for soluble CD14 in regulation of biological activity of systemic endotoxin. Clin. Diagn. Lab. Immunol. 6: 844–850. [PubMed] [Google Scholar]
  • Kelly CJ, Colgan SP, et al. 2012. Of microbes and meals: the health consequences of dietary endotoxemia. Nutr. Clin. Practice 27: 215–225. [CrossRef] [Google Scholar]
  • Kemp DM, 2013. Does chronic low-grade endotoxemia define susceptibility of obese humans to insulin resistance via dietary effects on gut microbiota? Adipocyte 2: 188–190. [CrossRef] [PubMed] [Google Scholar]
  • Lakatos PL, Kiss LS, et al. 2011. Serum Lipopolysaccharide-binding Protein and Soluble CD14 Are Markers of Disease Activity in Patients with Crohn’s Disease. Inflamm. Bowel Dis. 17: 767–777. [CrossRef] [PubMed] [Google Scholar]
  • Lamping N, Dettmer R, et al. 1998. LPS-binding protein protects mice from septic shock caused by LPS or gram-negative bacteria. J. Clin. Invest. 101: 2065–2071. [CrossRef] [PubMed] [Google Scholar]
  • Lassenius MI, Pietilainen KH, et al. 2011. Bacterial endotoxin activity in human serum is associated with dyslipidemia, insulin resistance, obesity, and chronic inflammation. Diabetes Care 34: 1809–1815. [CrossRef] [PubMed] [Google Scholar]
  • Laugerette F, Vors C, et al. 2011. Emulsified lipids increase endotoxemia: possible role in early postprandial low-grade inflammation. J. Nutr. Biochem. 22: 53–59. [CrossRef] [PubMed] [Google Scholar]
  • Laugerette F, Furet JP, et al. 2012. Oil composition of high-fat diet affects metabolic inflammation differently in connection with endotoxin receptors in mice. Am. J. Physiol. Endocrinol. Metab. 302: E374–386. [CrossRef] [PubMed] [Google Scholar]
  • Laugerette F, Alligier M, et al. 2014. Overfeeding increases postprandial endotoxemia in men: Inflammatory outcome may depend on LPS transporters LBP and sCD14. Mol. Nutr. Food Res. 58: 1513–1518. [CrossRef] [PubMed] [Google Scholar]
  • Laugerette F, Pineau G, et al. 2015. Endotoxemia analysis by the Limulus amoebocyte lysate assay in different mammal species used in metabolic studies J. Anal. Bioanalytical Tech., final revision. [Google Scholar]
  • Le Chatelier ENT, Qin J, Prifti E, et al. 2013. Richness of human gut microbiome correlates with metabolic markers. Nature 29: 541–546. [CrossRef] [PubMed] [Google Scholar]
  • Lecomte M, Bourlieu C, et al. 2015. Milk Polar Lipids Affect In Vitro Digestive Lipolysis and Postprandial Lipid Metabolism in Mice. J. Nutr. 145: 1770–1777. [CrossRef] [PubMed] [Google Scholar]
  • Lecomte M, Couedelo L, et al. 2016. Dietary emulsifiers from milk and soybean differently impact adiposity and inflammation in association with modulation of colonic goblet cells in high-fat fed mice. Mol. Nutr. Food Res. DOI:10.1002/mnfr.201500703. [Google Scholar]
  • Ley RE. 2010. Obesity and the human microbiome. Curr. Opin. Gastroenterol. 26: 5–11. [CrossRef] [PubMed] [Google Scholar]
  • Ley RE, Turnbaugh PJ, et al. 2006. Microbial ecology – Human gut microbes associated with obesity. Nature 444: 1022–1023. [CrossRef] [PubMed] [Google Scholar]
  • Libby P. 2002. Inflammation in atherosclerosis. Nature 420: 868–874. [CrossRef] [PubMed] [Google Scholar]
  • Lundman P, Boquist S, et al. 2007. A high-fat meat is accompanied by increased plasma interleukin-6 concentrations. Nutr. Metab. Cardiovasc. Diseas. 17: 195–202. [CrossRef] [Google Scholar]
  • Magné J, Mariotti F, et al. 2010. Early postprandial low-grade inflammation after high-fat meal in healthy rats: possible involvement of visceral adipose tissue. J. Nutr. Biochem. 21: 550–555. [CrossRef] [PubMed] [Google Scholar]
  • Mani V, Hollis JH, et al. 2013. Dietary oil composition differentially modulates intestinal endotoxin transport and postprandial endotoxemia. Nutr. Metab. 10: 6. [CrossRef] [PubMed] [Google Scholar]
  • Marshall JC, 2005. Lipopolysaccharide: an endotoxin or an exogenous hormone? Clin. Infect. Dis. 41: S470–480. [CrossRef] [PubMed] [Google Scholar]
  • Mathison JC, Tobias PS, et al. 1992. Plasma lipopolysaccharide (LPS)-binding protein. A key component in macrophage recognition of gram-negative LPS. J. Immunol. 149: 200–206. [PubMed] [Google Scholar]
  • Matsushita H, Ohta S, et al. 2010. Endotoxin tolerance attenuates airway allergic inflammation in model mice by suppression of the T-cell stimulatory effect of dendritic cells. Int. Immunol. 22: 739–747. [CrossRef] [PubMed] [Google Scholar]
  • Michalski MC, Genot C, et al. 2013. Multiscale structures of lipids in foods as parameters affecting fatty acid bioavailability and lipid metabolism. Progress Lipid Res. 52: 354–373. [CrossRef] [PubMed] [Google Scholar]
  • Moreno-Navarrete JM, Escote X, et al. 2013. A role for adipocyte-derived lipopolysaccharide-binding protein in inflammation- and obesity-associated adipose tissue dysfunction. Diabetologia 56: 2524–2537. [CrossRef] [PubMed] [Google Scholar]
  • Nappo F, Esposito K, et al. 2002. Postprandial endothelial activation in healthy subjects and in type 2 diabetic patients: Role of fat and carbohydrate meals. J. Am. College Cardiol. 39: 1145–1150. [CrossRef] [PubMed] [Google Scholar]
  • Neal MD, Leaphart C, et al. 2006. Enterocyte TLR4 mediates phagocytosis and translocation of bacteria across the intestinal barrier. J. Immunol. 176: 3070–3079. [CrossRef] [PubMed] [Google Scholar]
  • Osborn MJ, Rosen SM, et al. 1964. Lipopolysaccharide of the Gram-Negative Cell Wall. Science 145: 783–789. [CrossRef] [PubMed] [Google Scholar]
  • Pais de Barros JP, Gautier T, et al. 2015. Quantitative lipopolysaccharide analysis using HPLC/MS/MS and its combination with the limulus amebocyte lysate assay. J. Lipid Res. 56: 1363–1369. [CrossRef] [PubMed] [Google Scholar]
  • Pastor Rojo O, Lopez San Roman A., et al. 2007. Serum lipopolysaccharide-binding protein in endotoxemic patients with inflammatory bowel disease. Inflamm. Bowel Dis. 13: 269–277. [CrossRef] [PubMed] [Google Scholar]
  • Ross R, 1999. Atherosclerosis is an inflammatory disease. Am. Heart J. 138: S419–420. [CrossRef] [PubMed] [Google Scholar]
  • Schiffrin EJ, Parlesak A, et al. 2009. Probiotic yogurt in the elderly with intestinal bacterial overgrowth: endotoxaemia and innate immune functions. Br. J. Nutr. 101: 961–966. [CrossRef] [PubMed] [Google Scholar]
  • Sussman M. 2002. Academic: San Diego, CA. [Google Scholar]
  • Tobias PS, Mathison J, et al. 1992. Participation of lipopolysaccharide-binding protein in lipopolysaccharide-dependent macrophage activation. Am. J. Respiratory Cell Mol. Biol. 7: 239–245. [CrossRef] [Google Scholar]
  • Van Dielen FM, van’t Veer C, et al. 2001. Increased leptin concentrations correlate with increased concentrations of inflammatory markers in morbidly obese individuals. Int. J. Obes. Relat. Metab. Disord. 25: 1759–1766. [CrossRef] [PubMed] [Google Scholar]
  • Vors C, Gayet-Boyer C, et al. 2014. Produits laitiers et inflammation métabolique : quels liens en phase postprandiale et à long terme? Cah. Nutr. Diet. 50: 25–38. [CrossRef] [Google Scholar]
  • Vors C, Pineau G, et al. 2015. Postprandial Endotoxemia Linked With Chylomicrons and Lipopolysaccharides Handling in Obese Versus Lean Men: A Lipid Dose-Effect Trial. J. Clin. Endocrinol. Metab. 100: 3427–3435. [CrossRef] [PubMed] [Google Scholar]
  • Vreugdenhil AC, Rousseau CH, et al. 2003. Lipopolysaccharide (LPS)-binding protein mediates LPS detoxification by chylomicrons. J. Immunol. 170: 1399–1405. [CrossRef] [PubMed] [Google Scholar]
  • Wurfel MM, Kunitake ST, et al. 1994. Lipopolysaccharide (LPS)-binding protein is carried on lipoproteins and acts as a cofactor in the neutralization of LPS. J. Exp. Med. 180: 1025–1035. [CrossRef] [PubMed] [Google Scholar]
  • Zhang HS, DiBaise JK, et al. 2009. Human gut microbiota in obesity and after gastric bypass. Proc. Natl. Acad. Sci. USA 106: 2365–2370. [CrossRef] [Google Scholar]

Cite this article as: Marie-Caroline Michalski, Cécile Vors, Manon Lecomte, Fabienne Laugerette. Dietary lipid emulsions and endotoxemia. OCL 2016, 23(3) D306.

All Tables

Table 1

Effect of test meal composition on postprandial endotoxemia in human studies. Adapted from Vors et al. (2014).

All Figures

thumbnail Fig. 1

Pro-inflammatory events induced by plasma lipopolysaccharides (LPS). Adapted from Laugerette et al. (2011); Vors et al. (2014). If reaching the bloodstream, LPS are taken up by a specific transport glycoprotein, the lipopolysaccharide-binding protein (LBP), towards immune cells (such as macrophages). Immune cell activation requires a specific molecular complex consisting of the membrane form of the cluster of differentiation 14 (mCD14), the Toll-Like Receptor 4 (TLR4) and the Myeloid Differentiation protein-2 (MD2). The mCD14 is a glycoprotein able to bind the LPS-LBP complex, which can then fix on the TLR4 receptor and the co-receptor MD2 and then mediate signal transduction via the activation of NF-κB (Nuclear Factor-κB). This signalization cascade results in the secretion of proinflammatory cytokines (IL-6, TNF-α, IL-1β, etc.).

In the text
thumbnail Fig. 2

Postprandial endotoxemia and associated inflammation induced by the intestinal transcellular passage of bacterial LPS during lipid absorption (adapted from Vors et al., 2014). During a massive influx of dietary fatty acids in the postprandial phase, the LPS originated from the small intestine can be absorbed thanks to a transcellular passage during the intestinal absorption of dietary lipids. LPS are then transported in the bloodstream thanks to chylomicrons secreted in the postprandial phase. The circulating LPS are then partially taken up by specific transport proteins as described in Figure 1, therefore generating inflammatory events in the vascular endothelium and peripheral tissues.

In the text
thumbnail Fig. 3

Summary of recent studies about postprandial endotoxemia in lean, overweight or obese men (Laugerette et al., 2011, 2014; Vors et al., 2015). Upper panel: lean to overweight subjects were submitted to the same postprandial test before and after 8 weeks of overfeeding. Lower panel: lean and obese subjects were submitted to two different postprandial tests varying by the amount of fat in the meal.

In the text
thumbnail Fig. 4

Examples of supramolecular organization of lipid molecules in food products, oil-in-water emulsions and emulsifiers, which can impact on digestive and postprandial events. Adapted from Michalski et al. (2013).

In the text
thumbnail Fig. 5

Summary of recent studies about the impact of oil composition, emulsified structure and the type of phospholipid emulsifier on endotoxemia and inflammation (Laugerette et al., 2011, 2012; Lecomte et al., 2016). (A) Catheterized rats were forced fed with saline, sunflower oil + saline or an emulsion of sunflower oil in saline using soybean phospholipids (lecithin) as emulsifier and blood was drawn along the postprandial phase. (B) Mice were fed with high-fat diets varying in fat source during 8 weeks and different markers of endotoxemia and inflammation were measured in plasma and adipose tissue. (C) Mice were fed with a synthetic high-fat diet based on palm oil during 8 weeks, or with a modified diet in which 1.2% of the triglycerides have been replace with 1.2% of polar lipids (PL, mainly phospholipids) from either milk or soybean. PC: phosphatidylcholine, PE: phosphatidylethanolamine, PI: phosphatidylinositol, SM: sphingomyelin.

In the text

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