Medical Hypotheses (2004) 63, 724–730

http://intl.elsevierhealth.com/journals/mehy

Do surface-active lipids in food increasethe intestinal permeability to toxic substancesand allergenic agents?

N.-G. Ilb€acka,b,*, M. Nybloma, J. Carlforsc, B. Fagerlund-Aspenstr€oma,S. Tavelinc, A.W. Glynna,d

a Toxicology Division, National Food Administration, P.O. Box 622, S-751 26, Uppsala, Swedenb Department of Medical Sciences, Section of Infectious Diseases, Uppsala University, S-751-85,Uppsala, Swedenc Department of Pharmacy, Uppsala University, Uppsala, Swedend Department of Environmental Toxicology, Uppsala University, Uppsala, Sweden

Received 1 August 2003; accepted 19 October 2003

Summary The incidence of many common diseases has increased during the last decades. High fat intake is a riskfactor for many diseases. We propose that some of the negative effects of fat are caused by lipid-induced damage ofthe gastrointestinal epithelium, thus compromising the epithelial function as a barrier for passage of toxic substancesand allergenic agents to the circulatory system. Monoglycerides (MGs), phospholipids and fatty acids (FAs) are surface-active molecules that in pharmaceutical studies act as permeability enhancers for hydrophilic drugs with lowabsorption. Three possible mechanisms were proposed: (a) lipid-induced alterations in intracellular events may causedestabilization of tight junctions between the GI epithelial cells, (b) lipids may destabilize cell membranes, (c) lipidscause intestinal cell damage, which increase the permeability of the GI epithelium. These “side effects” of lipids maypartly explain the association between fat intake and disease observed in epidemiological studies.

�c 2004 Published by Elsevier Ltd.

Introduction

Food components present in the gastrointestinal(GI) tract can markedly alter the bioavailability ofchemical compounds in food. Food components inthe GI tract have impacts on transit profiles, pH,and solubilizing capacity, which subsequently mayaffect bioavailability [1]. Complexing agents,present in food, have extensively been studied as

* Corresponding author. Tel.: +46-18-17-57-50.E-mail address: nils-gunnar.ilback@slv.se (N.-G. Ilb€ack).

0306-9877/$ - see front matter �c 2004 Published by Elsevier Ltd.doi:10.1016/j.mehy.2003.10.037

absorption modifiers of positively charged, andpoorly absorbed, water-soluble compounds. Forexample, low-molecular-weight organic acids, suchas citric acid, enhance the absorption of aluminumin food, probably by increasing the aluminum sol-ubility [2,3]. Other complexing agents, such asphytate, may decrease the absorption of divalentmetal ions, by decreasing the free ion concentra-tion in the intestinal lumen [4].

The integrity of the GI tract epithelium is es-sential for blocking the passage of toxic substancesand allergenic agents from the GI lumen to the

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systemic circulation. Consequently, food compo-nents that compromise the integrity of the GI epi-thelium could be involved in the induction ofdiseases. The incidence of many common diseaseshas increased during the last decades, but only afew environmental factors have been identified asrisk factors. High intake of some lipids and ac-companying obesity are associated with a multi-tude of diseases [5–14]. Lipids, such asmonoglycerids (MGs), fatty acids (FAs) and phos-pholipids are surface-active compounds that showpermeability-enhancing effects in pharmaceuticalstudies [1]. For decades, FA and MG formulationshave been used by the medical industry in order toenhance the intestinal absorption of drugs. Thisstrategy has, depending on the candidate sub-stance, been more or less successful in clinicalsettings.

Although lipids per se are not regarded as toxicto the mucosal cells of the GI tract, we hypothesizethat surface-active lipids present in food maycompromise GI tract integrity. As a consequence,the lipids cause an increased passage of food-bornetoxic substances and allergic agents from the in-testinal lumen to the circulatory system. As abackground to our hypothesis, we first give a shortdescription of the structure of the intestinal mu-cosa and the barriers restricting and regulatingintestinal absorption of drugs and other chemicals.A summary of lipid digestion in the GI tract is alsogiven. We then review the literature dealing withfactors affecting the permeability of the intestinalepithelium, with special focus on effects of sur-face-active lipids. Finally, we discuss the possibil-ity that these surface-active components of foodmay enhance the absorption of toxic substancesand allergenic agents, a possible mechanism,among others, behind the observed associationsbetween high fat intake and increased risk of dis-eases such as cancer, cardio-vascular disorders,diabetes, etc.

Structure of the intestinal mucosa

Enterocytes make up over 90% of the cell popula-tion in the epithelium of the intestinal wall [15].The intestinal epithelium is shaped into finger- andleaf-shaped villi, a structure which makes the sur-face of absorption as large as possible. Enterocytesare produced through mitotic division at the baseof the villi, and the maturing cells continuouslymigrate up to the tips of the villi, where they afterapproximately three days are discarded into thebulk of the intestine [15]. The most distinctive

feature of the enterocyte is the apical or brushborder membrane,which is composed of denselypacked microvilli. External to the microvilli, theglycocalyx or “fuzzy coat” is situated. The fuzzycoat is mainly composed of glycoproteins and isproduced continuously by the enterocytes. It hasbeen suggested that it may protect the intestinalmucosa and aid in the digestion of food. The sur-face of the epithelium is also covered by mucus,which is separated from the bulk of the intestine bya stagnant layer of water called the aqueousboundary layer (ABL) [15]. Other important cell-types in the intestinal epithelium are gobletcells and M-cells [16]. The mucus-producing gobletcells are intermingled with the absorptive cells.The mucus can act as a physical, protective barrierthat binds ions and other agents. M-cells play animportant role in the uptake of antigens, macro-molecules and particulate matter [16].

Barriers restricting and regulatingintestinal absorption

The mucus layer, forming the protective barrieradjacent to the apical cell membrane, may act as adiffusional barrier, especially for large molecules,such as peptides and proteins. However, the mucuslayer seems to be of limited significance as a bar-rier for diffusion of low molecular weight com-pounds [17].

The single layer of intestinal epithelial cells isregarded as the main rate-limiting barrier regard-ing passage of pharmaceutical drugs and othercompounds from the intestinal lumen to the cap-illaries of the lamina propria [1,18]. An importantcomponent of this barrier is the tight junctionsconnecting the most apical parts of the epithelialcells. Tight junctions are also an important part ofthe junctional complex, which mediate adhesionbetween the cells [1,18].

In order to cross the epithelium, a substance hasto permeate through the apical and basolateral cellmembranes (by the transcellular route) or betweenthe cells (by the passive paracellular route)[15,19]. Since the lipid-rich cell membranes areconsidered almost impermeable to hydrophiliccompounds, many of these substances are re-stricted to the paracellular pathway where thetight junctions are the rate-limiting barriers [19].Similarly, ionised compounds do not partition intothe lipophilic cell membranes of the epithelialcells, and their passive transport therefore alsooccurs mainly through aqueous, paracellularpathways between the epithelial cells [20]. Most

726 Ilb€ack et al.

compounds are, however, excluded from theparacellular route because of their size. The tightjunctions limit the permeability of molecules witha radii larger than 3–8 �A [21]. In addition to thesize restriction, there is also a charge restriction.The paracellular route is selective for cations,which possibly may be explained by the net nega-tive charge of the tight junctions [21].

One of the main functions of the enterocytes isto transport nutrients, and in that process to ex-press nutrient-specific carriers that mediate activetransport of molecules, such as sugars and amino-acids. It has been shown that some synthesiseddrugs, especially those that are structural similarto the natural substrates of the transcellular car-riers, can utilise these transport mechanisms[22,23]. However, in most cases absorption ofnonessential compounds occurs by a passive diffu-sion process, along a concentration gradient [24].

Lipid digestion and absorption

According to Swedish intake data, the daily averageintake of fat is 72 g for women and 92 g for men,which is approximately 34% of the daily energy in-take for both women and men [25]. The main die-tary fat sources are cooking fat (17%), meat andpoultry (14%), sausages, cheese, milk, soured milkand cakes (3%) [26]. Dietary fat consists mainly oftriglycerids (TGs) [27]. These molecules consist ofglycerol joined with FAs of different length (num-ber of carbon atoms). The average daily dietaryintake of FAs are highest for oleic acid (C18:l),23.4 g for Swedish women and 30.8 g for men perday, and palmitic acid (C16:0), 15.6 g for womenand 20.4 g for men per day [25].

The digestion of fat is initiated by a gastricphase where 20–30% of the total lipolysis occur[28]. Preduodenal lipases hydrolyses the TGs todiglycerides (DGs), monoglycerides (MGs) and freefatty acids (FFAs). The hydrolysis occurs at allthree TG positions, with the sn-1 and sn-3 positionsslightly favoured [29]. In the duodenum, pancreaticlipase also cleaves TGs in the sn-1 and sn-3 posi-tions. Pancreatic cholesterol esters hydrolasecompletely hydrolyses cholesterol esters into FFAsand free cholesterol. Dietary phospholipids arehydrolysed by activated pancreatic phospholipaseA2 yelding 1-lysophospholipids and FFAs. In theduodenum, ionised FFAs and 2-MGs enter into bilesalt micelles mixed with phospholipids. The for-mation of the mixed micelles further disperses theTGs and DGs into even smaller oil droplets than inthe stomach, and thus creating a greater surface of

contact between the fat and the aqueous phase. Afurther hydrolysis of the sn-1 and sn-3 position ofDGs and TGs produce FAs and sn-2 MGs [27]. At thisstage the lipid physical state is still an emulsionwith a core of TG, vitamin, and cholesterol esters,and a surface of phospholipids, cholesterol, bilesalts, and colipase. Similar to their function in thefood industry, the MGs produced during fat diges-tion facilitate emulsification [27].

It has been estimated that approximately 75% ofthe initial ingested TGs are hydrolysed to 2-MGsand absorbed by the enterocytes [27]. Upon entryinto the enterocyte, the 2-MGs are rapidly resyn-thesised to TGs for further transport to thebloodstream in the form of chylomicra. Clinicaltrials of radiolabeled TGs provide conclusive evi-dence that MGs are absorbed intact into the in-testinal wall, and that the 2-MG pathway is themajor route of fat absorption for man during nor-mal digestion and absorption of dietary TGs [30].

Surfactants

Substances, such as short-chain FAs and alcohols,are soluble in water as well as in organic solvents[31]. The hydrocarbon part of the molecule ac-counts for its solubility in organic solvents, whilethe polar ACOOH or AOH group, with its high af-finity to water, provides the solubility in aqueoussolutions. In an interface between air (alterna-tively oil) and water, the hydrophilic head groupsof the compounds are dissolved in the aqueousphase while the lipophilic hydrocarbon chains aredissolved in the vapour (oil) phase. This arrange-ment is energetically more favorable than com-plete solution in either phase. The strongadsorption of such molecules at surfaces or inter-faces is termed surface activity. The surface-activemolecules are called surfactants and contain bothpolar and non-polar parts [31].

In dilute solution the surfactants are dissolved asmonomers. At fairly well defined concentrations,however, abrupt changes in several physical prop-erties, such as osmotic pressure, electrical con-ductance and surface tension, take place. Thesurfactant molecules form organized aggregates,micelles. In aqueous solution the molecules orientthemselves with their polar groups outwards, whilein organic solutions reverse micelles are formedwith the hydrocarbon chains oriented at the sur-face of the aggregates. The concentration at whichthe micelle formation becomes appreciable iscalled the critical micelle concentration (CMC)[31].

Association between fat intake and diseases 727727

Surfactants are able to stabilize emulsions, i.e.,blends of substances that in general are not mis-cible, due to the fact that they can exist in theinterface between the phases of the substancesinvolved thereby reducing their interfacial tension.Therefore, surfactants are frequently engaged infood emulsions as additives. However, not allsurfactants in food are additives. There exist manyfood emulsions produced by nature itself, con-taining naturally occurring surfactants, such aslipids and proteins. One example is a fat emulsionstabilized by casein and fatty acids, milk. In fact,the food industry extracts, purifies and engagesmany of these “natural” surfactants as additives infood products. Examples are glycerides derivedfrom vegetable oils. Another example is lecithin,phospholipids with excellent emulsifying proper-ties, which are obtained from egg yolk and soybeans [31].

Do lipids affect the intestinalpermeability?

We hypothesize that surface active lipids, formedduring normal lipid digestion, may enhance thepermeability of the intestinal epithelium to water-soluble and poorly absorbed compounds in foodthat may be toxic or cause allergic reactions. Ourhypothesis is mainly based on the absorption-enhancing properties of MGs, FFAs and phospho-

Table 1 Examples of lipids acting as absorption enhancer

Lipid Model compoun

Hexanoic acid, sodium hexanoate (C6) CefoxitinOctanoic acid, sodium octanoate (C8) CefoxitinSodium octanoate CefoxitinSodium decanoate (C10) Fluorescein, cyc

disaccharideDecanoic acid, sodium decanoate Cefoxitin, ampi

glycyrrhizinSodium laurate (C12) Fluorescein, cycLauric acid, sodium laurate Cefoxitin, phenMyristic acid, sodium myristate (C14) CefoxitinPalmitic acid, sodium palmitate (C16) CefoxitinStearic acid, sodium stearate (C18) CefoxitinOleic acid, sodium oleate (C18) Insulin, phenolEicosapentaenic acid (C20) InsulinDocosahexaenoic acid (C22) Insulin

Glycerol monohexanoate (C6) Nonapeptides dMixed glycerides (C6) Nonapeptides dMixed glycerides (C8/10) Nonapeptides dGlyceryl-1-monooctaonate CefoxitinMedium-chaInglycerides Phenol red

lipids shown in numerous studies of drug absorptionboth in vitro and in vivo (Table 1). Moreover, an invitro study indicate that surfactants, used as foodadditives, may enhance the intestinal permeabilityto food allergens [32].

Experimental studies have shown that MGs, FFAsand phospholipids enhance absorption of hydro-phobic drugs in vitro in the Caco-2 cell mono-layermodel, in vivo in the rat jejunum and colon bothafter oral and rectal administration. The absorp-tion enhancement potency decreases in the orderFAs>MGs> diglycerids. Consequently, the ab-sorption enhancement effect of triglycerides isdependent on the presence of lipase in the GI tract[33].

The medium-chained fatty acid capric acid isused as an absorption enhancer in drug productsmarketed in Japan, Denmark and Sweden [34].Sodium caprate exert absorption-enhancing effectsin human colon [35], and studies on healthy vol-unteers have shown that sodium octanoate mayincrease the rectal absorption of cefoxitin [36].

In situ and in vivo studies in rodents, of perme-ability-enhancing properties of FAs commonlypresent in food, suggest that eicosapentaeonic acid(EPA, C20) and docosahexaenoic acid (DHA, C22)are more potent permeability enhancers of insulinthan oleic acid (OA, C18) [37]. Among medium-chained fatty acids, the enhancement in uptake ofcalcein was found to be dependent on the chainlength of the fatty acid (C8¼C10>C12) [38]. So-dium salts of fatty acids was more efficient than

s of hydrophilic pharmaceutical drugs

d Model system Refs.

In vivo rat [33,50]In vivo rat [33,50]Human [36]

lopeptide, heparin Caco-2 cells [34,51,52]

cillin, phenol red, In vivo rat [33,50,53,54]

lopeptide Caco-2 cells [34,51]ol red, glycyrrhizin In vivo rat [33,54]

In vivo rat [33]In vivo rat [33]In vivo rat [33]

red, glycyrrhizin In vivo rat [54,55]In vivo rat [55]In vivo rat [55]

DAVP In vivo rat [56]DAVP In vivo rat [56]DAVP In vivo rat [56]

In vivo rat [57]In vivo rat [58]

728 Ilb€ack et al.

the free fatty acids when absorption enhancementof cefoxitin was studied in rats, especially withsodium myristate (C14), palmitate (C16) and stea-rate (C18) [33].

Published studies indicate three basic ways bywhich the intestinal brush border may be affectedby MGs and FAs. The first possibility is that thelipids affect the tight junctions (TJ) directly orindirectly, causing enhanced absorption by theparacellular route. Secondly, lipids may destabilizemembranes and thus, enhancing the absorption bythe transcellular route. Thirdly, lipids may be cy-totoxic, causing cell damage that disturbs the in-tegrity of the gastrointestinal epithelium, and thusalso increasing the intestinal permeability to wa-ter-soluble compounds.

Tight junctions; in vitro studies of permeabilityenhancing effects of medium-chain FFAs, suggestthat FFA-induced alterations in intracellular eventsmay mediate an increase in paracellular perme-ability to poorly absorbed hydrophilic substances[34,39]. In this case, FFAs affect the phospholi-pase-C (PLC)-dependent signaling pathway whichhas been implicated in the assembly, regulationand barrier properties of the tight junction [40].Another proposed mechanism for absorption en-hancing effects through the paracellular pathway isthe formation of complexes between FAs and Ca2þ,causing depletion of extracellular Ca2þ. This hasbeen shown to destabilise the tight junctions[38,41].

Destabilizing cell membranes; the second wayfor MGs and FFAs to enhance the permeability isdestabilisation of the membranes, achieved by in-teraction between MGs and FAs with proteins andlipids in the membranes, (e.g., extraction of cho-lesterol from membranes) [42]. For instance, brushborder membrane [BBM] vesicles from rat colon,with their protein and lipid component labelledwith fluorescent probes, were used in examiningthe perturbing effects of caprate (salt of fatty acidC10:0) and caprylate (salt of fatty acid C8:0) on themembranes [43]. Caprate interacted with bothproteins, and lipids and caprylate mainly withproteins, causing disordering of the BBM [43].

Cytotoxicity; “Ordinary” dietary fat in generalcause superficial intestinal cell damage [44,45],which may increase the paracellular permeabilityto water-soluble compounds. MGs and FAs areknown to cause damage to cell membranes, due totheir high surface activities [41,46]. For instance,sodium caprate (over 24 mM) causes membranesolubilization, cell extrusion, and cell death [41]. Amixture of phosphatidylcholine (PC):MG caused ir-reversible damage to the Caco-2 cell monolayerat a concentration of 8 mM [47]. The molecule

1-octanoyl-glycerol (a main component in thePC:MG mixture) is known to dissolve cholesterolefficiently from cell membranes. From these find-ings it does not seem unreasonable to assumethat an increased load of MGs and FAs may havetransient negative effects on integrity of thegastro-intestinal epithelium [47].

The gastrointestinal mucosa is continuously ex-posed to noxious compounds either ingested orproduced endogenously, and these compounds maynegatively affect the epithelial cells, thus impair-ing the integrity of the epithelium. This is thereason why the mucosal epithelium has a high ca-pacity to regenerate, by cell division and migrationof cells from the crypts to the surface of the mu-cosa, in order to maintain the integrity of the ep-ithelium [48]. The epithelium also have a capacityto repair defects in the protective epithelium byrestitution, where viable cells adjacent to the de-fect flatten, extend lamellipodia and migrate toreseal the epithelial lining. Restitution may play animportant role in repairing the multiple superficialdefects in the epithelial lining that occur duringthe normal course of ingestion and absorption offood [48].

As proposed above, ingestion lipid-rich foodsmay be one reason for the observed damage of theintestinal epithelium during food ingestion. Theseeffects may transiently increase the permeability ofthe epithelium causing an increased passage of ionsand other hydrophilic molecules during and afterthe meal until the epithelial barrier is fully re-paired. These effects of lipids are supported bydamage of the epithelial lining of the jejunal villoustips in rats perfused with emulsified oleic acid(40mM) [44,49]. During perfusion with 20 and 40mMoleic acid emulsions the intestinal permeability toEDTA increased and full restitution of the epitheliallining took about 50 min after resumption of theperfusion [44,49]. Since the concentrations of oleicacid used in the study was within the physiologicalrange, it was concluded that the findings may havesome relevance to events occurring during thenormal course of digestion and absorption [44].

Lipids are essential for life but the surface-ac-tive nature of many of these compounds may causenegative effects if over-consumption occurs. Wepropose that high intake of lipids could compro-mise the barrier function of the GI epithelium, thuscausing an increased passage of toxic substancesand allergenic agents from the GI lumen to thecirculatory system. If this hypothesis is validated inthe future, the absorption enhancing effects oflipids may be one additional reason for the rec-ommendation to change the dietary habits towardslower fat intakes.

Association between fat intake and diseases 729729

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