nutrient signaling: evolutionary origins of the immune
TRANSCRIPT
Nutrient Signaling: Evolutionary Origins of the Immune-Modulating Effects of Dietary FatAuthor(s): Joe Alcock, Melissa L. Franklin, and Christopher W. KuzawaReviewed work(s):Source: The Quarterly Review of Biology, Vol. 87, No. 3 (September 2012), pp. 187-223Published by: The University of Chicago PressStable URL: http://www.jstor.org/stable/10.1086/666828 .Accessed: 29/08/2012 00:30
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NUTRIENT SIGNALING: EVOLUTIONARY ORIGINS OF THEIMMUNE-MODULATING EFFECTS OF DIETARY FAT
Joe AlcockDepartment of Emergency Medicine, University of New Mexico
Albuquerque, New Mexico 87131 USA and Emergency Medicine Service,New Mexico VA Health Care System
Albuquerque, New Mexico 87108 USA
e-mail: [email protected]
Melissa L. FranklinDepartment of Biology, University of New Mexico
Albuquerque, New Mexico 87131 USA
Christopher W. KuzawaDepartment of Anthropology and the Institute for Policy Research, Northwestern University
Evanston, Illinois 60208 USA
Keywordsevolution, inflammation, fatty acids, microbiota, cardiovascular disease,
nutrition
abstractMany dietary fatty acids (FA) have potent effects on inflammation, which is not only energetically
costly, but also contributes to a range of chronic diseases. This presents an evolutionary paradox: Whyshould the host initiate a costly and damaging response to commonly encountered nutrients? Wepropose that the immune system has evolved a capacity to modify expenditure on inflammation tocompensate for the effects of dietary FA on gut microorganisms. In a comprehensive literature review,we show that the body preferentially upregulates inflammation in response to saturated FA thatpromote harmful microbes. In contrast, the host often reduces inflammation in response to the manyunsaturated FA with antimicrobial properties. Our model is supported by contrasts involving shorter-chain FA and omega-3 FA, but with less consistent evidence for trans fats, which are a recent additionto the human diet. Our findings support the idea that the vertebrate immune system has evolved acapacity to detect diet-driven shifts in the composition of gut microbiota from the profile of FAconsumed, and to calibrate the costs of inflammation in response to these cues. We conclude byextending the nutrient signaling model to other nutrients, and consider implications for drugdiscovery and public health.
The Quarterly Review of Biology, September 2012, Vol. 87, No. 3
Copyright © 2012 by The University of Chicago Press. All rights reserved.
0033-5770/2012/8703-0001$15.00
Volume 87, No. 3 September 2012THE QUARTERLY REVIEW OF BIOLOGY
187
Introduction
CLASSICALLY, fatty acids (FA) have beenunderstood as influencing risk for car-
diovascular disease through effects on cir-culating lipoprotein cholesterol profiles(Remig et al. 2010). Saturated FA tend toelevate low-density lipoprotein cholesterol,while polyunsaturated fatty acids (PUFA)increase high-density lipoprotein choles-terol and reduce trigylcerides (Schaefer2002). Although these effects on circulat-ing lipids are well established, dietary fatshave additional effects on inflammationthat are important in the progression ofmany chronic degenerative diseases (Rid-ker et al. 2000; Kennedy et al. 2009). Inparticular, consumption of saturated fats hasbeen associated with the metabolic syndromeand heart disease, while unsaturated fats, par-ticularly the omega-3 PUFA, generally have theopposite effects (Esposito and Giugliano2006).
Although these inflammatory effects ofcertain dietary fats are increasingly appreci-ated, the ubiquity of the body’s inflamma-tory and metabolic response to foods poses amystery. Because organisms are limited inthe pool of energy and substrate available toallocate across the body’s various functions,it follows that expenditure on one functionnecessarily comes at a cost to others (Wil-liams 1966; Stearns 1992). As a result, organ-isms will tend to evolve strategies that avoidmobilizing costly functions without a reason.Inflammation involves production of toxicoxygen species, acute phase reactants, andchemokines that recruit and activate macro-phages, representing a costly mobilization ofhost resources (Lochmiller and Deerenberg2000; Zuk and Stoehr 2002; McDade 2003;Hanssen et al. 2004; Sorci and Faivre 2009).The mystery of widespread and costly diet-induced inflammation is further highlightedby the variety of diseases, including obesity,metabolic syndrome, diabetes, and athero-sclerosis, which are worsened by chronic in-flammation (Ridker et al. 2000; Esposito andGiugliano 2006). Thus, we are faced with anevolutionary paradox: why should the hostinitiate a costly and injurious response tocommonly encountered nutrients?
In this paper, we hypothesize that theinflammatory effects of saturated FA and theanti-inflammatory effects of many unsatu-rated FA are not accidents, but instead re-flect the evolution of host immune responsesto dietary signals of impending shifts in gutmicrobiota and related risks of infection.This hypothesis emerges from the observa-tion that nutrients are not simply energysources for the host, but also influence thegrowth and invasiveness of microorganisms inthe gastrointestinal tract (Keeney and Finlay2011; Wu et al. 2011). Dietary FA, in particular,have important effects on gut microbiota, withsome FA providing innate defenses againstpathogens, while others promote pathogencolonization and growth. As we outline below,these various effects of FA on gut microbiotasuggest a novel hypothesis to explain thehealth effects of dietary fats.
We first review the pathways by whichspecific FA promote or inhibit the survivaland growth of species of bacteria and thatinfluence translocation of bacteria into thehost circulation. Based on these effects, weoutline a hypothesis for the evolution ofinflammatory and anti-inflammatory re-sponses that depend on FA chain lengthand the nature of double bonds between car-bon atoms. We next systematically review therelevant literature to test these hypotheses,finding 67 published studies of FA antimicro-bial activity and 56 published studies of directFA effects on inflammation that meet our in-clusion criteria. We conclude by extending ourmodel to carbohydrates and micronutrients,outline testable hypotheses, and consider thebroader implications for human nutrition,drug discovery, and public health.
How Dietary Fatty Acids Affect theImmune System and Gut Microbiota
modulation of inflammation bydietary lipids
Dietary fats generally occur as triglycer-ides, which consist of a glycerol backbonejoined to three FA. Lipases in the mouthand gastrointestinal tract hydrolyze triglyc-erides into mono- and diglycerides andfree FA. All of these fat-like compounds aredescribed by the term “lipids,” which also
188 Volume 87THE QUARTERLY REVIEW OF BIOLOGY
includes phospholipids and cholesterol. Ataxonomy of FA and their dietary sources isdisplayed in Table 1. Diet-derived FA can
have markedly different effects on humanhealth and immune activation dependingon their structure (Tables 2 and 3). Fatty
TABLE 1Nomenclature and dietary sources of fatty acids
SaturationStatus Subtype
Double BondPosition
Double BondConfiguration(trans or cis)
CommonName
LipidNumber
RepresentativeDietary Source
Saturated(no doublebondsbetweencarbons)
Short-/Medium-Chain �12carbon chainlength (SCFA/MCFA)
Butyric acid C4:0 Butter, Parmesancheese
Caproic acid C6:0 Goat MilkCaprylic acid C8:0 MilkCapric acid C10:0 CoconutLauric acid C12:0 Coconut, Breast milk
Long-Chain �12carbon chainlength
Myristic acid C14:0 Butter, Nutmeg
Palmitic acid C16:0 Palm oilStearic acid C18:0 Animal fat
Unsaturated(at least 1doublebondsbetweencarbons)
Monounsaturated1 carbon-carbondouble bond(MUFA)
cis Myristoleic acid C14:1 Milk fat (uncommon)
cis Palmitoleic acid C16:1 Animal fat,Macadamia oil
cis Oleic acid C18:1 Olive oilcis Ricinoleic acid C18:1 Castor oiltrans trans Vaccenic C18:1 Dairy products
Polyunsaturated �
1 carbon-carbondouble bond(PUFA)
Omega-6 (finaldoublebond on 6thcarbon frommethyl end)
all cis Linoleic acid C18:2 Corn oil
Omega-6 all trans Linolelaidic C18:2 Hydrogenatedvegetable oil
Omega-3 (finaldoublebond on 3rdcarbon frommethyl end)
all cis Linolenic acid C18:3 Flaxseed oil
Omega-6 all cis Gamma linolenicacid
C18:3 Evening primrose oil
Omega-6 all cis Arachidonic acid C20:4 EggsOmega-3 all cis Eicosapentaenoic
acidC20:5 Salmon, Seaweed
Omega-3 all cis Docosahexanoicacid
C22:6 Marine fish oils
Note: The numeral following the “C” indicates the number of carbons in the fatty acid. The numeral following the colonindicates the number of double bonds in the fatty acid (degree of unsaturation).
September 2012 189NUTRIENT SIGNALING
acids affect inflammatory gene expressionin humans by regulating transcription fac-tors such as nuclear factor kappa B (NF-�B) or peroxisome proliferator-activatedreceptors (PPAR). Gene expression is alsomodulated by fatty acid-sensing G-proteinreceptors and signal transduction pathwaysthat depend on membrane lipids and lipidrafts (Jump 2004). Through these path-ways, some saturated FA (lipids with car-bon chains that are fully saturated withhydrogen atoms) amplify proinflammatorygene expression in innate immune cells(Schwartz et al. 2010). Saturated FA havewide-ranging effects on inflammation, in-cluding activation of monocytes, oxygenradical production in vascular endothelialcells, and insulin resistance in muscle andother tissues. By contrast, unsaturated FA,particularly the omega-3 PUFA, have beenshown to reduce the activity of NF-�B,PPARs, and membrane-dependent proteinkinases, thus decreasing the downstreamexpression of inflammatory genes (Zhao etal. 2007; Wong et al. 2009; Holzer et al.2011). As one example, a recently charac-terized G-protein receptor was shown toact as a sensor for omega-3 PUFA in hu-man and mouse intestinal and adiposecells (Miyauchi et al. 2010); its activationinhibited NF-�B with anti-inflammatory ef-fects in mice (Oh et al. 2010). There areseveral important exceptions to this gen-eral pattern of increased proinflammatorysignaling by saturated FA and inhibition ofinflammation by unsaturated FA. Someshort-chain fatty acids (SCFA), although
fully saturated, have the capacity to reduceinflammation in human cells (Hoshimotoet al. 2002; Wanten et al. 2002). Mean-while, many omega-6 PUFA, although un-saturated, have been reported to generatemetabolites and induce gene expressionwith proinflammatory effects (Teitelbaumand Walker 2001).
How Dietary Fatty Acids Modify Riskof Bacterial Invasion in the GutAlthough the inflammatory effects of FA
are well documented, it is less well appre-ciated that they also influence bacterialsurvival and proliferation in the gastroin-testinal tract. Besides serving as a potentialgrowth substrate and carbon source, a keymechanism by which FA affect bacterialgrowth and invasiveness is their ability to breakdown the microbial cell membrane (Chen etal. 2011). FA have a methyl group and a car-boxyl group at each terminus and vary in thelength of their carbon chains and in the pres-ence of double bonds (Figure 1). Some ofthese structural features give antibacterial, an-tifungal, and antiprotozoan activity to FA (Des-bois and Smith 2010). Antimicrobial effects oflipids are incompletely understood, but appearto exert their effect, in part, by modifyingmembrane fluidity and disrupting cell mem-branes of certain bacteria (Desbois and Smith2010; Chen et al. 2011).
Some bacteria are sensitive to membrane-destabilizing effects that occur after the incor-poration of exogenous FA into membranephospholipids. Increased membrane fluidity
TABLE 2Effects of dietary lipids on human cardiovascular disease and cardiac risk factors
Lipid Class Effect References
Long-chain saturated Increased risk of obesity, metabolic syndromeIncreased risk of cardiovascular disease
(Mozaffarian et al. 2010)(Hu et al. 1999)
Short- and medium-chainsaturated
No increased risk of cardiovascular diseaseDecreased metabolic syndrome, improved insulin sensitivity
(Hu et al. 1999)(Nagao and Yanagita 2010)
Polyunsaturated Reduced cardiovascular riskReduced obesity and improved insulin sensitivity
(Mozaffarian et al. 2010)(Summers et al. 2002)
Omega-3 polyunsaturated Reduced cardiovascular riskImproved insulin sensitivity
(Einvik et al. 2010)
Trans unsaturated Increased risk of cardiovascular diseaseIncreased diabetes
(Remig et al. 2010)(Kummerow 2009)
190 Volume 87THE QUARTERLY REVIEW OF BIOLOGY
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onn
eutr
oph
ilsu
pero
xide
prod
ucti
on
(Hor
ani
etal
.20
06)
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awet
al.
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)(L
ain
eet
al.
2007
)(H
uan
get
al.
1997
)(N
auro
thet
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2010
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rutc
hle
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dyet
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cont
inue
d
September 2012 193NUTRIENT SIGNALING
and permeability caused by free FA have beenshown to result in cell lysis, interfere with enzy-matic processes and oxidative phosphoryla-tion, and inhibit microbial growth (Desboisand Smith 2010). Inhibition of pathogens bythe products of digestion of dietary fat, partic-ularly milk fat, has been demonstrated in mam-malian herbivores (Canas-Rodriguez andSmith 1966; Sun et al. 2007) and in humans(Hamosh et al. 1999; Isaacs 2001). Free FA andmonoglycerides with strong antimicrobial ac-tivity are generated by the action of gastric lip-ases on milk fat when infants consume breastmilk (Isaacs et al. 1990). Antimicrobial FA de-rived from breast milk kill viral, bacterial, andprotozoan pathogens (Thormar et al. 1987;Hamosh et al. 1999; Isaacs 2001). Shorter-chain FA and monoglycerides in milk andsome other foods (Table 1) have surfactantactivity that can increase permeability of thecell membranes of gram negative bacteria suchas Escherichia coli, Yersinia enterocolitica, andSalmonella sp. (Altieri et al. 2009), the grampositive bacteria Streptococcus spp. andStaphylococcus aureus, and the yeast Candida(Kabara et al. 1972). The observation that
TA
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vey
etal
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mer
owet
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iddi
qui
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adgo
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al.
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rans
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sion
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xan
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rmat
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erin
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oun
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ndi
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tty
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.Figure 1. Space Fill Diagrams of
Representative Fatty AcidsSpace fill and structural diagrams are shown for
four representative fatty acids. Myristic acid is a 14carbon saturated FA. Oleic acid is a 18 carbon mono-unsaturated FA with a single double bond. The dou-ble bond introduces a kink in the conformation ofthe FA. Elaidic acid is a 18 carbon monounsaturatedtrans FA. The trans isomerization induces a more lin-ear conformation similar to saturated FA. Linolenicacid, a polyunsaturated omega-3 FA, has three doublebonds between carbons.
194 Volume 87THE QUARTERLY REVIEW OF BIOLOGY
breast milk digestion generates free FAwith strong bactericidal effects may explainsome of the infant health benefits ofbreastfeeding and illustrates how the anti-bacterial activity of FA and monoglyceridescould be under selection due to their in-fluence on infectious mortality.
Additional evidence for the evolution ofhost defenses that harness the natural an-timicrobial properties of lipids come fromstudies that document an abundance ofantimicrobial FA in tears, nasal secretions,and on the skin, locations where host cellsand microorganisms interact (Do et al. 2008;McCusker and Grant-Kels 2010). Fatty aciddefense of the skin is a phenomenon thatbegins before birth, since vernix caseosa, thesubstance that covers neonates at birth, con-tains lipids with antimicrobial activity (Tollinet al. 2005). After birth, antimicrobial FAsecreted by sebaceous glands are bactericidalto pathogens and promote the growth ofbeneficial microorganisms (Ko et al. 1978;Wille and Kydonieus 2003). These variousstudies of skin and breast milk lipids showthat the antibacterial activities of FA andmonoglycerides are sufficiently potent tohave been harnessed by natural selection tohelp protect the host from invasive patho-gens.
The importance of FA in pathogen sur-vival is illustrated by the fact that many bac-teria respond to destabilizing FA, low pH,and other stresses by modifying or replacingcell membrane FA as a defense mechanism(Keweloh and Heipieper 1996). For instance,bacterial enzymes hydrogenate unsaturatedmembrane lipids and isomerize unsaturatedFA from the cis to trans conformation (Chiouet al. 2004; Yuk and Marshall 2004). The result-ing saturated and trans FA increase the rigidityof cell membranes and can reduce bacterialsusceptibility to lysis. Because many bacterialstrains lack the enzymes to interconvertmembrane FA, saturated or trans fats fromfood serve as freely available membrane sub-strates with built-in resistance to host antibac-terial defenses, including gastric acid (Sun etal. 2003; Yuk and Marshall 2004) and inhib-itory FA liberated by gastric lipases (Isaacs2001).
effects of dietary fats on the gutmicrobiota
Given the powerful effects that various FAhave on the growth, inhibition, and killing ofbacteria that occur in the gut, it is not sur-prising that the composition of dietary lipidsconsumed can affect the colonization andcomposition of the gut microbiota (Ander-sen et al. 2011; Jumpertz et al. 2011; Wu et al.2011). The gut microbiota is a diverse assem-blage of microorganisms that number asmany as 100 trillion, with the majority resi-dent in the colon (Sekirov et al. 2010). Oneclue that the gut microbiota may help modu-late postprandial inflammation is the findingthat consumption of fat causes endotoxin, thecell wall constituent of gram negative bacteria,to translocate from the lumen of the intestineinto the bloodstream (Cani and Delzenne2009). Outside of the intestinal lumen, endo-toxin is a powerful proinflammatory stimu-lus (Cani and Delzenne 2009; Schwartz et al.2010). However, dietary fats have many ad-ditional effects on the gut microbiota besidesserving as a conduit for bacterial antigens inchylomicrons to enter the circulation. Forexample, breast milk lipids, along with milkoligosaccharides and immunoglobulins, arethought to prevent intestinal colonization ofdangerous microbes and help establish theneonatal microbiota (Goldman 2002; Ander-sen et al. 2011).
Along similar lines, Finch proposed thatbecause bacteria often contaminate meat, in-flammation from dietary fat could have pro-vided protection from foodborne illness(Finch 2007). Foodborne illness is a ubiquitousthreat to human survival, and has shaped di-etary practices of many cultures (Billing andSherman 1998). Bacterial colonization of thegut is only half the story, however, because dietalso shapes the composition of indigenous gutmicrobiota (Jumpertz et al. 2011). Alterationof gut microbiota, known as dysbiosis, canalso create opportunities for pathobionts, or-ganisms that are generally benign coinhab-itants of the gut, but that have pathogenicpotential (Lee and Mazmanian 2010). Di-etary FA and lipid metabolites of commensalbacteria have been shown to promotegrowth and virulence of some potential
September 2012 195NUTRIENT SIGNALING
pathogens (Keeney and Finlay 2011) andmay also induce disease from pathobionts. Inaddition, altered gut flora have been shownto be an important cause of gut-derived sep-sis that can lead to death (Shimizu et al.2011). Thus, two related dietary risk fac-tors—inoculation of new pathogens andchanges in the composition of resident gutbacteria—may provide ongoing selectivepressure for an immune modulating func-tion of fat.
Inflammation generated by certain bacte-ria, and by the nutrients that feed them, hasthe effect of eliciting host functions that re-duce the likelihood of overgrowth at the in-testinal epithelium, and may help preventbacteria from invading epithelial cells andsterile tissues. An increased abundance ofpathogens and pathobionts stimulate a hostimmune response via activation of patternrecognition receptors of the innate immunesystem (Schwartz et al. 2010). One host re-sponse to dysbiosis is the production of anti-microbial peptides, including � defensin and� defensin and phospholipase A2. These an-timicrobial peptides have innate immuneactivity that prevents luminal bacteria fromattaching to the epithelium (Mukherjee etal. 2008; Ciccia et al. 2010). Defensins areproduced constitutively by intestinal epithe-lial cells, generating an antimicrobial envi-ronment that helps maintain homeostasis atthe intestinal mucosa. Inducible defensin ex-pression, with direct antibiotic-like effects,occurs during overgrowth by pathogens andcommensal bacteria (O’Neil et al. 1999). In-flammation also increases the production ofsecretory mucin by specialized intestinalcells. During infection, the host increases theproduction of mucin, thus causing sheddingof the mucus layer and associated bacteria(Bergstrom et al. 2010). In addition to inflam-mation caused by bacterial antigens, nutrientsalso induce the proinflammatory pathways thatresult in production of defensins and expres-sion of mucin genes (Figure 2; O’Neil et al.1999; Ahn et al. 2005). The pathways in-volved in intestinal inflammation also inducethe production of monocyte chemokine pro-tein-1, which recruits phagocytic cells thatengulf and neutralize pathogens. Throughthis mechanism, consumption of proinflam-
matory fats results in increased phagocytosisof microbes by activated monocytes and mac-rophages (Schaeffler et al. 2009). Exposureto pathogenic microorganisms and FAcauses increased oxygen uptake and produc-tion of oxygen radicals (e.g., superoxide),which increase the bactericidal capacity ofactivated neutrophils and macrophages(Wanten et al. 2002; Sorci and Faivre 2009).Increased oxidative load during inflamma-tion generates strongly antimicrobial oxi-dized lipids, which are important in innateimmune defense of the host (Khovidhunkitet al. 2004; Schwartz et al. 2010).
the nutrient signaling model ofdietary inflammation
In light of the broad effects of specificnutrients on microbes and innate immunity,we propose that the vertebrate immune sys-tem has evolved the ability to use nutrients,and the bacterial metabolites of nutrients, asan “early warning system” that signal im-pending changes in infectious risk at themicrobial-epithelial interface. Nutrients thatprovide growth substrates and competitiveopportunities for potential pathogens re-quire a compensatory mobilization of im-mune resources. The host thus responds to
Figure 2. Two Possible Causes forInflammatory Effects of DietaryNutrients
(a) A dietary nutrient can result in inflammationwhen it changes the composition of gut microbiotaand increases the flow of bacterial lipopolysaccharideinto the blood, resulting in immune activation. Asecond inflammatory pathway, the focus of the pres-ent model (b), occurs when cell membrane receptorsinteract with fatty acids, resulting in an immune re-sponse that does not require microorganism interme-diaries. The direct immune effects of fatty acids occurin parallel with diet-induced changes in gut microbi-ota and provide an early signal of changing risk fromthe gut.
196 Volume 87THE QUARTERLY REVIEW OF BIOLOGY
these nutrients by upregulating inflamma-tion. Because inflammation is costly anddamaging, the vertebrate immune systemhas also evolved a capacity to suppress in-flammation in response to nutrients that in-hibit harmful gut microbes (Figure 3). Thismodel leads to the prediction that there willbe a correspondence between the effects of acommonly encountered FA on harmful gutmicrobes and its direct signaling effect onhost inflammation. The model is formalizedin the following testable hypotheses:
1) Commonly consumed fatty acids thatenhance the colonization and growth ofpathogens and pathobionts will have directproinflammatory effects in the host.
2) Commonly consumed fatty acids thatsuppress the colonization and growth ofpathogens and pathobionts will have directanti-inflammatory effects in the host.
Testing the HypothesisHere we compile findings from the pub-
lished literature to test this model and its pre-dictions. All dietary FA can be separated intotwo categories, saturated or unsaturated, de-pending on the presence or absence of doublebonds. Because saturated and unsaturated FAboth occur in meat, as well as breast milk andmany vegetable foods, they are thought to havebeen commonly consumed throughout hu-man evolution (Eaton et al. 1988). Because oftheir ubiquity, and because saturation status isa key determinant of biologic activity, thesenutrients provide a critical test of Hypotheses 1and 2. For each comparison of saturated versusunsaturated FA documented in the literature,we first review what is known about the effectof each lipid on pathogenic gut microorgan-isms, which sets up the expectations from ourmodel for differences in inflammation (caused
Figure 3. How Direct Nutrient-Based Immune Signaling is Hypothesized to have EvolvedNutrients that are commonly encountered in the diet consistently increase or decrease risk of microbial
overgrowth and infection (top pane). Through time, the vertebrate immune system obtained the ability to usethese nutrients as cues of impending changes in microbial risk, allowing anticipatory up- or down-regulationof inflammation in anticipation of impending diet-induced microbial changes.
September 2012 197NUTRIENT SIGNALING
directly by FA, independent of microbes) be-tween saturated and unsaturated FA and otherlipid classes. We then review the literature toevaluate whether the direct inflammatory andanti-inflammatory effects of each lipid are con-sistent with our model of nutrient signaling.
Search Methodology for LiteratureReporting Microbial and DirectInflammatory Effects of Dietary
LipidsWe conducted a comprehensive literature
review using PubMed and ISI Web of Knowl-edge. We searched for the terms “fatty acid,”specific names of lipids and lipid categorieswith the terms “antimicrobial,” “antibacte-rial,” “inhibit,” or “growth” with “bacteria,”“pathogen,” “parasite,” “fungi,” or specificnames of enteric pathogens and potentialpathogens. Literature cited in review articlesof these topics was also included. Of thesestudies, we included in our analyses that sub-set of studies that: reported comparisons ofthe in vitro effects of purified lipids in differ-ent classes (below) on the survival of potentialpathogens; included species that are potentialgastrointestinal pathogens of humans, identi-fied as such in a major gastroenterology text-book (Feldman et al. 2010); and includedeven-numbered carbon chain length FA andmonoglycerides, which constitute greater than95% of the FA typically consumed in the hu-man diet. Because methods and protocols varyacross studies, comparisons were limited towithin-study contrasts of the effects of differentlipid classes. In each study that met the inclu-sion criteria, the “more antimicrobial” and“less antimicrobial” lipid class was determinedby tallying the direction of the differences be-tween individual lipids. Studies that reportedequal effects of different FA were also noted;these were divided into “equal NI” (noninhibi-tory) and “equal” (both lipids show pathogeninhibition). Lipid comparisons performed un-der comparable conditions (e.g., same dosage,organism, pH) within a study were aggregatedto display relative numbers of differences ineach direction and the number of equal com-parisons.
To maximize the number of potential com-parisons, we employed the total evidence ap-proach (Kluge 2004; Sherman et al. 2008), in
which all information is considered and dataare not weighed by quality of evidence. Al-though the total evidence approach is subjectto the biases and errors of individual studies,we deemed it preferable to the alternative“quality analysis” method (Sherman et al.2008) in part because of the difficulty of objec-tively evaluating the relative validity and qualityof the widely heterogeneous data sets that wereviewed.
A similar search protocol was followed tocompare the direct effects of FA on inflam-mation. This search used the PubMed and ISIWeb of Knowledge terms: “fatty acids” and “in-flammation.” Additional searches were per-formed with individual names of FA. Again, welimited comparisons to within-study compari-sons of the direct inflammatory effects of dif-ferent lipids. Studies were included if theyreported differences in the in vitro direct in-flammatory effects (i.e., not mediated by bac-teria or lipopolysaccharide) between lipidclasses on human cells and platelets. Outcomesincluded activation of innate immune path-ways involving nuclear receptors NF-�B andPPAR�, mitogen-activated protein kinases(MAPK) and Jun kinases (JNK), and down-stream expression of pro- and anti-inflammatory cytokines, tumor necrosis factor(TNF), monocyte chemoattractant protein-1(MCP-1), white blood cell and endothelial cellexpression of adhesion molecule (E-selectin,VCAM, and ICAM), platelet activation, and ox-ygen radical production. All searches were lim-ited to studies published in English.
We used these data to test Hypotheses 1and 2. Specifically, when microbial proper-ties of multiple lipid classes were reported inthe same study, we hypothesized that themore antimicrobial lipid class would have amore prominent, direct anti-inflammatoryeffect than its counterpart. Published studiesallowed us to test our hypotheses using themain comparison of unsaturated versus sat-urated FA. These data also allowed us topursue additional more nuanced contrastswithin subgroups of saturated FA: short- andmedium-chain length versus long-chain satu-rated FA (see Table 1 for definitions) and forsubgroups of unsaturated FA. The additionalcontrasts of unsaturated FA were omega-3versus omega-6 PUFA, polyunsaturated ver-
198 Volume 87THE QUARTERLY REVIEW OF BIOLOGY
sus monounsaturated FA, and unsaturatedFA with all cis versus all trans double bonds.
All comparisons were made between FA ofthe same chain length, unless otherwise noted.When available, monoglycerides and diglycer-ides were also compared. For studies that metour criteria and showed a difference in patho-gen inhibition or inflammation, the directionof the difference was recorded and tabulatedin a contingency table. With individual studiesas the unit of comparison, a Fisher’s exact test(Stata 11.0) was used to test for an associationbetween antimicrobial activity and inflamma-tory effect of lipids.
Findingsfindings: do antimicrobial fats havedirect anti-inflammatory effects on
the host?Comparison 1. Unsaturated versus
Saturated Fatty AcidsIn data pooled from all studies meeting
our criteria, the antimicrobial activity of un-saturated FA exceeded that of saturated FAin a majority of observations (Figure 4a).Unsaturated FA had stronger antibacterialeffects than saturated FA in 27 studies; sixstudies showed stronger bacterial inhibitionby saturated FA; equivalent inhibition wasreported in one study (Table 4). Overall,gram positive bacteria were more sensitive toantimicrobial effects of unsaturated FA (Ma-rounek et al. 2003). For instance, Kabara etal. (1972) showed that three of five unsatu-rated 18 carbon FA were potent inhibitorsof Group A Streptococcus, with linoleic acid(C18:2) showing activity at the lowest concen-tration (0.089 �moles/ml). The saturated 18carbon FA failed to inhibit pathogen growth, asdid the two 18 carbon unsaturated trans fats atmuch higher concentrations (�3.5 �moles/ml) (Kabara et al. 1972). Under certain growthconditions, some FA were found to promotethe growth of bacteria by providing a sourceof carbon. Saturated FA tended to be moreeffective growth promoters than unsaturatedFA, resulting in exponential replication ofStaphylococcus aureus that had been exposedto a growth inhibitor (Altenbern 1977a).Some unsaturated FA affect innate immunityby affecting the ability of pathogens to ad-
here to intestinal epithelial binding sites.Monounsaturated oleic acid and the polyunsat-urated linoleic acid and linolenic acid havebeen shown to prevent pathogen binding tohuman intestinal cells in culture. These unsat-urated FA have been reported to enhance thecompetitive exclusion of Salmonella by the com-mensal Lactobacillus bacteria (Muller et al.2011).
Saturated FA tend to induce inflammationby activating nuclear transcription factorssuch as nuclear factor kappa B (NF-�B) andperoxisome proliferator-activated receptors(PPAR) (Schwartz et al. 2010). Saturated FAare also ligands for mitogen-activated pro-tein kinase (MAPK) (Ishiyama et al. 2010)and Jun kinases (JNK) (Håversen et al. 2009)and other protein kinases that regulate nu-clear factor transcription activity. SaturatedFA tend to generate the expression of proin-flammatory cytokines and chemokines suchas TNF-�, IL-8, IL-1�, IL-6, and MCP-1 (Hå-versen et al. 2009; Kopp et al. 2009). Satu-rated FA have also been reported to induceinflammation and insulin resistance by in-creasing the activity of pattern recognitionreceptors, such as toll-like receptors (TLR)(Shi et al. 2006). Inflammatory gene expres-sion is also modulated by fatty acid-sensingG-protein receptors and signal transductionpathways that depend on membrane lipidsand lipid rafts (Holzer et al. 2011) and by theaction of fatty acid metabolites such as cer-amide (Håversen et al. 2009). Using a mousemodel, Holzer et al. demonstrated that inflam-matory signaling depends on membrane in-corporation of saturated versus unsaturatedlipids (Holzer et al. 2011). Because of theireffects on membrane fluidity, saturated fattyacid-enriched membranes cause c-SRC tyro-sine kinases to cluster in the cell membrane,where they activate JNK, eliciting the proin-flammatory signaling that is associated withobesity, atherosclerosis, and metabolic syn-drome. Increased membrane fluidity causedby unsaturated FA prevents c-SRC clustering,thus inhibiting JNK inflammation (Holzer etal. 2011).
Comparisons of the direct effects of theseFA on human cell inflammation were gener-ally in agreement with the expectations ofthe nutrient signaling model. In most pub-
September 2012 199NUTRIENT SIGNALING
lished studies, saturated FA usually causedproinflammatory signaling, while unsatu-rated lipids often had the opposite effect.Saturated FA caused more inflammationthan unsaturated FA in 21 studies; four stud-ies showed the opposite relationship; and
one study had mixed results (Shaw et al.2007; Table 3). In this comparison, the ten-dency for FAs with promicrobial effects totrigger direct proinflammatory on host cellswas strongly statistically significant (p�0.001,Fisher’s exact test, Table 5).
Figure 4. Aggregated Lipid-Lipid Comparisons of Antimicrobial ActivityComparing the relative antimicrobial effects in vitro of different lipid classes evaluated under identical
conditions (see methods for details). Lipid contrasts include: (a) unsaturated versus saturated; (b) short- andmedium-chain versus long-chain saturated; (c) polyunsaturated versus monounsaturated; (d) omega-3 versusomega-6 polyunsaturated; and (e) cis versus trans unsaturated.
200 Volume 87THE QUARTERLY REVIEW OF BIOLOGY
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cher
etal
.19
76;
Lac
eyan
dL
ord
1981
;va
nde
rK
ooij
and
Hijn
en19
88;
Pets
chow
etal
.19
96;
Mba
ndi
etal
.20
04)
MG
C18
:1M
GC
18:2
�M
GC
18:0
Lis
teri
am
onoc
ytog
enes
no
(1)
(Wan
get
al.
1993
)
Not
e:C
prec
eded
byM
Gin
dica
tes
am
onog
lyce
ride
.C
prec
eded
byD
Gin
dica
tes
digl
ycer
ide.
Mon
o-an
ddi
glyc
erid
esw
ere
only
com
pare
dto
oth
erm
ono-
and
digl
ycer
ides
.N
opr
efix
indi
cate
sa
free
fatt
yac
id.
C18
:1is
olei
cac
idun
less
oth
erw
ise
spec
ified
.Pa
thog
enn
ames
hav
ebe
enup
date
d.*P
ath
ogen
slis
ted
show
edse
nsi
tivi
tyto
atle
ast
one
fatt
yac
idin
the
com
pari
son
.
September 2012 201NUTRIENT SIGNALING
Comparison 2. Short- and Medium-ChainSaturated Fatty Acids versus Long-Chain
Saturated Fatty AcidsMany studies reported differences in the an-
timicrobial activity of saturated FA dependingon chain length. In pooled data, the bacteri-cidal activity of shorter-chain saturated FAtended to exceed that of longer-chain satu-rated FA (Figure 4b). Although the potency ofindividual FA is highly variable, shorter-chainFA (four to 12 carbons in length) were shownto inhibit a wide variety of gastrointestinalpathogens. The FA in this group with the mostpotent inhibitory effect were 8-to-12 carbon FAand monoglycerides (Batovska et al. 2009). Forexample, lauric acid (C12) inhibits Listeriamonocytogenes with a minimum inhibitory con-centration of 31–40 �g/ml (Mbandi et al.2004; Batovska et al. 2009), and the C12monoglyceride kills Staphylococcus aureus at8–25 �g/ml (Kelsey et al. 2006; Batovska et al.2009). Escherichia coli, like some other gramnegative bacteria, are resistant to many FA, butshowed inhibition by caprylic acid (C8) at aminimum concentration of 300–850 �g/ml(Marounek et al. 2003). Meanwhile, long-chain saturated FA (more than 12 carbons)were often inactive against these pathogens.Inhibition of potential pathogens by shorter-chain FA is not limited to direct antimicrobial
effects. Short-chain fatty acids (SCFA) pro-duced by commensal bacteria have beenshown to displace pathogens such as Salmonellatyphimurium from intestinal cell binding sitesalong the gut epithelium (Cox et al. 2008).SCFA also prevented the growth of patho-genic organisms by decreasing intestinal pH(Lin et al. 2008) and interfering with thecapacity of enteric pathogens to invade intes-tinal cells (Van Deun et al. 2008). Overall,short- and medium-chain FA and monoglyc-erides had stronger antimicrobial activitythan long-chain saturated FA in 35 studies;longer-chain saturated FA were more antimi-crobial in five studies, and two studiesshowed equivalent inhibition (Table 6).
The tendency of saturated FA to directly in-duce host inflammation appears to be influ-enced by the carbon chain length, with onestudy finding evidence for proinflammatory ef-fects on JNK limited to long-chain saturatedfat (with more than 16 carbons) (Holzer etal. 2011). Shorter-chain saturated FA failed toelicit proinflammatory signaling in this cell-based model. Additional anti-inflammatoryeffects of shorter-chain FA occur becausethese FA are ligands for G-protein receptorsthat tend to elicit anti-inflammatory signalingfunctions (Cavaglieri et al. 2003; Hamer et al.2008).
TABLE 5Contingency table analysis of lipid effects on pathogens and inflammation
Fatty acidMore antimicrobial
lipid*More inflammatory
lipid** p value***
Saturated 7 21 p � 0.001Unsaturated 27 5
Long-Chain Saturated 7 6 p � 0.005Short-/Medium-Chain Saturated 35 3
Omega-6 7 17 p � 0.02Omega-3 15 8
Monounsaturated 12 11 p � 0.094Polyunsaturated 27 9
trans fatty acid 1 4 p � 0.28cis fatty acid 7 4
*Data points are publications comparing the antimicrobial activity of lipids (references are listed in Tables 4, 6–8). Publica-tions showing equal and mixed antimicrobial activity between lipid categories were included with first FA in each comparison:saturated, long-chain saturated, monounsaturated, and omega-6 FA, respectively.**Data points are publications comparing the direct inflammatory effects of lipids (references are listed in Table 3).***Fisher’s exact test.
202 Volume 87THE QUARTERLY REVIEW OF BIOLOGY
TA
BL
E6
Ant
imic
robi
alac
tivity
ofSC
FA/M
CFA
and
long
-cha
insa
tura
ted
fatty
acid
s
Shor
t/m
ediu
mfa
tty
acid
stud
ied
Ant
imic
robi
alco
mpa
riso
nL
ong-
chai
nsa
tura
ted
fatt
yac
ids
stud
ied
Pat
hoge
nsin
hibi
ted
byFA
*
Are
shor
tan
dm
ediu
mch
ain
lipid
sm
ore
anti
mic
robi
al?
Ref
eren
ces
even
C4:
0–C
12:0
even
MG
C8:
0–M
GC
12:0
�ev
enC
14:0
–C20
:0ev
enM
GC
14:0
–MG
C18
:0A
erob
acte
rA
erom
onas
hydr
ophi
laC
ampy
lbac
ter
jeju
niC
andi
daal
bica
nsB
acill
usce
reus
Clo
stri
dium
botu
linum
Clo
stri
dium
perf
ring
ens
Esch
eric
hia
coli
Hel
icob
acte
rpy
lori
Lis
teri
am
onoc
ytog
enes
Prot
eus
vulg
arus
Salm
onel
laen
teri
ditis
Salm
onel
laty
phim
uriu
mSt
aphy
loco
ccus
aure
usSt
rept
ococ
cus
Gro
upA
Stre
ptoc
occu
sG
roup
BVi
brio
chol
erae
yes
(35)
(Has
sin
enet
al.
1951
;C
anas
-Rod
rigu
ezan
dSm
ith
1966
;Fu
ller
and
Moo
re19
67;
Gal
brai
thet
al.
1971
;Sa
lan
itro
and
Weg
ener
1971
;K
abar
aet
al.
1972
;Fa
yan
dFa
rias
1975
;A
lten
bern
1977
a;M
iller
etal
.19
77;
Beu
chat
1980
;L
acey
and
Lor
d19
81;
Hog
anet
al.
1988
;va
nde
rK
ooij
and
Hijn
en19
88;
Aba
bouc
het
al.
1992
;W
ang
and
Joh
nso
n19
92;
Wan
get
al.
1993
;Pe
tsch
owet
al.
1996
;Pe
tron
eet
al.
1998
;Sp
ron
get
al.
1999
;B
ergs
son
etal
.20
01;
Spro
ng
etal
.20
01;
Ber
gsso
net
al.
2002
;L
eeet
al.
2002
;M
arou
nek
etal
.20
03;
Sun
etal
.20
03;
Kit
ahar
aet
al.
2004
;M
ban
diet
al.
2004
;Sk
riva
nov
aet
al.
2004
;Sk
riva
nov
aet
al.
2005
;K
else
yet
al.
2006
;T
hor
mar
etal
.20
06;
Skri
van
ova
and
Mar
oun
ek20
07;
Sun
etal
.20
07;
Bat
ovsk
aet
al.
2009
;H
uan
get
al.
2011
)ev
enC
4:0–
C12
:0M
GC
12:0
–MG
C16
:0D
GC
12:0
–DG
C16
:0
�ev
enC
14:0
–C18
:0M
GC
14:0
MG
C16
:0D
GC
14:0
DG
C16
:0
Gia
rdia
lam
blia
Myc
opla
sma
bovi
sM
ycop
lasm
atu
berc
ulos
isSt
aphy
loco
ccus
aure
usSt
rept
ococ
cus
Gro
upB
no
(5)
(Will
ett
and
Mor
se19
66;
Kon
doan
dK
anai
1972
;K
ondo
and
Kan
ai19
77;
Nai
doo
1981
;R
ein
eret
al.
1986
)
C4:
0–C
12:0
�C
14:0
Ente
roco
ccus
faec
alis
Lis
teri
am
onoc
ytog
enes
no
(2)
(Sun
etal
.20
02)*
*(K
inde
rler
eret
al.
1996
)
Not
e:C
prec
eded
byM
Gin
dica
tes
am
onog
lyce
ride
.C
prec
eded
byD
Gin
dica
tes
digl
ycer
ide.
Mon
o-an
ddi
glyc
erid
esw
ere
only
com
pare
dto
oth
erm
ono-
and
digl
ycer
ides
.N
opr
efix
indi
cate
sa
free
fatt
yac
id.
*Pat
hog
ens
liste
dsh
owed
sen
siti
vity
toat
leas
ton
efa
tty
acid
inth
eco
mpa
riso
n.P
ath
ogen
sth
atfa
iled
tosh
owin
hib
itio
nby
eith
erca
tego
ryof
FAin
clud
edSa
lmon
ella
typh
imur
ium
,Sal
mon
ella
ente
ritid
is,
and
E.co
li01
57:H
7(L
eeet
al.
2002
)an
dK
lebs
iella
pneu
mon
iae
and
Esch
eric
hia
coli
(Hog
anet
al.
1988
).**
Mix
edre
sult
sby
path
ogen
,gr
oupe
dw
ith
“no.
”En
tero
cocc
usfa
ecal
is(S
trep
toco
ccus
faec
alis
)w
asm
ore
sen
siti
veto
shor
t-ch
ain
fatt
yac
ids.
September 2012 203NUTRIENT SIGNALING
As predicted by our model, long-chain satu-rated FA were more directly inflammatorythan shorter-chain saturated FA in six studieswhile only three studies reported the oppositefindings (Table 3). The inverse relationshipbetween inflammation and antimicrobial activ-ity was statistically significant (p�0.005, Fis-her’s exact test, Table 5).
Comparison 3. Omega-3 versus Omega-6PUFA
The position of the C-C double bondfrom the methyl end of PUFA (the third orsixth position) determines whether a FA isan omega-3 FA or omega-6 FA. Omega-3FA have been shown to kill and inhibitbacteria more readily than omega-6 FA in15 studies; five studies had the oppositefindings; and two studies reported mixedor equal inhibition of bacteria (Table 7).In pooled data from 20 of 22 studies, mostcomparisons showed greater pathogen inhibi-tion by omega-3 FA than by omega-6 FA (Fig-ure 4c). Two studies, excluded from Figure 4cbecause they did not provide the exact identi-fication of pathogen strains, also showedstronger bacterial inhibition by omega-3 FA(Heczko et al. 1979; Lacey and Lord 1981).Heczko et al. showed that of 242 strains ofStaphylococcus aureus, most strains were sensi-tive to the omega-3 linolenic acid (C18:3)at a minimum concentration of 0.19 mmol/Lwhile most strains were inhibited by theomega-6 linoleic acid at a minimum con-centration of 6.25 mmol/L (Heczko et al.1979). Some studies reported the oppositefindings (Kabara et al. 1972), but most pub-lications that met inclusion criteria favoredpathogen killing by omega-3 FA (Table 7).
In addition to changes in chemokine, cy-tokine, and adhesion molecule expressioncaused by PUFA, the omega-3 and omega-6FA also undergo metabolism to pro- andanti-inflammatory eicosanoids that are in-volved in the progression of atherosclerosisand insulin resistance (Das 2010). Fatty acidsynthesis pathways begin with so-called essen-tial 18 carbon FA linoleic acid (omega-6)and linolenic acid (omega-3) that cannot besynthesized in humans de novo and thus mustbe obtained in the diet. These FA undergoconversion by elongases and desaturases to 20
carbon PUFA arachidonic acid and eicosapen-taenoic acid, respectively. The omega-3 FA ei-cosapentaenoic acid undergoes preferentialmetabolism to anti-inflammatory eicosanoids,including leukotrienes, prostacyclins, lipoxins,protectins, and maresins. The metabolic path-way utilizing omega-6 arachidonic acid,meanwhile, often generates proinflammatoryeicosanoids (Teitelbaum et al. 2001). The eico-sanoid products of omega-6 metabolism areresponsible for symptoms of inflammation—e.g., fever—and modulate the intensity andduration of inflammation (Calder 2002).Omega-3 FA metabolites—e.g., resolvins andprotectins—are important in resolving inflam-matory processes (Calder 2002). Decreased in-flammation from eicosanoids derived fromomega-3 FA compared to omega-3 FA is inline with the antimicrobial activity of its FAprecursors.
As predicted by our model, in 17 studies,omega-6 were more directly inflammatorythan omega-3 FA (Table 3), while six studieshad the opposite results and two studies hadmixed findings (Shaw et al. 2007; Nauroth etal. 2010). When omega-6 and omega-3 FAwere compared, there was a statistically sig-nificant inverse relationship between antimi-crobial activity and inflammation (p�0.02,Fisher’s exact test, Table 5).
Comparison 4. Polyunsaturated versusMonounsaturated Fatty Acids
Monounsaturated fatty acids (MUFA) oc-cupy an intermediate position between the sat-urated FA and FA with multiple double bonds(PUFA). In general, PUFA usually killed orinhibited sensitive gastrointestinal pathogensat lower concentrations than MUFA of thesame chain length (Kabara et al. 1972).Growth of Listeria monocytogenes is inhibited byPUFA in milk fat, including linolenic acid(C18:3), an omega-3 FA that was antibacterialat 2 �g/ml (Petrone et al. 1998). This differ-ence is repeated in most of the pooled lipid-lipid comparisons (Figure 4d). By comparison,the MUFA oleic acid (C18:1) inhibited Listeriaat a much higher concentration, 200 �g/ml(Petrone et al. 1998). PUFA were more antimi-crobial than MUFA in 27 of 39 studies(Table 8). Of the remainder, eight studies re-
204 Volume 87THE QUARTERLY REVIEW OF BIOLOGY
TA
BL
E7
Ant
imic
robi
alac
tivity
ofpo
lyun
satu
rate
dan
dm
onou
nsat
urat
edfa
ttyac
ids
ofsa
me
chai
nle
ngth
Pol
yuns
atur
ated
fatt
yac
ids
stud
ied
Ant
imic
robi
alco
mpa
riso
nM
onou
natu
rate
dfa
tty
acid
sst
udie
dP
atho
gens
inhi
bite
dby
FA*
Are
PU
FAm
ore
anti
mic
robi
al?
Ref
eren
ces
C18
:2,
C18
:3C
18:3
gam
ma
linol
enic
C20
:2,
C20
:3,
C20
:4,
C20
:5C
22:5
�C
18:1
C20
:1C
22:1
Bac
tero
ides
frag
ilis
Bac
illus
cere
usC
ampy
loba
cter
jeju
niC
lost
ridi
umbo
tulin
umC
lost
ridi
umpe
rfri
ngen
sC
rypt
ospo
ridi
umpa
rvum
Gia
rdia
lam
blia
Hel
icob
acte
rpy
lori
Ente
roco
ccus
Lis
teri
am
onoc
ytog
enes
Myc
opla
sma
bovi
sM
ycop
lasm
atu
berc
ulos
isSt
aphy
loco
ccus
aure
usSt
rept
ococ
cus
Gro
upA
Stre
ptoc
occu
sG
roup
B
yes
(27)
(Ful
ler
and
Moo
re19
67;
Kab
ara
etal
.19
72;
Kon
doan
dK
anai
1972
;K
abar
aet
al.
1973
;G
utte
ridg
eet
al.
1974
;B
utch
eret
al.
1976
;A
lten
bern
1977
b;K
ondo
and
Kan
ai19
77;
Nai
doo
1981
;C
ampb
ell
etal
.19
83;
Kn
app
and
Mel
ly19
86;
Roh
rer
etal
.19
86;
Hog
anet
al.
1988
;T
hom
pson
etal
.19
90;
Cro
uch
etal
.19
91;
Aba
bouc
het
al.
1992
;W
ang
and
Joh
nso
n19
92;
Th
omps
onet
al.
1994
;K
hul
usi
etal
.19
95;
Petr
one
etal
.19
98;
Dili
kaet
al.
2000
;Sp
ron
get
al.
2001
;Su
net
al.
2003
;Z
hen
get
al.
2005
;K
else
yet
al.
2006
;Sc
hm
idt
and
Kuh
len
sch
mid
t20
08)
C16
:3C
18:2
,C
18:3
�C
16:1
C18
:1ol
eic
C18
:1ri
cin
olei
c
Aer
omon
ashy
drop
hila
Bac
illus
cere
usC
andi
dasp
.C
lost
ridi
umpe
rfri
ngen
sEs
cher
ichi
aco
liL
iste
ria
mon
ocyt
ogen
esSa
lmon
ella
ente
ridi
tisSt
aphy
loco
ccus
aure
us
no
(8)
(Will
ett
and
Mor
se19
66;
Dye
and
Kap
ral
1981
;va
nde
rK
ooij
and
Hijn
en19
88;
Spro
ng
etal
.19
99;
Mba
ndi
etal
.20
04;
Skri
van
ova
etal
.20
05;
Des
bois
etal
.20
08;
Ch
enet
al.
2011
)
MG
C18
:2C
18:2
,C18
:3�
MG
C18
:1C
18:1
Can
dida
albi
cans
Gia
rdia
lam
blia
Stap
hylo
cocc
usau
reus
no
(4)
(Lac
eyan
dL
ord
1981
;R
ein
eret
al.
1986
;W
ang
etal
.19
93;
Hua
ng
etal
.20
10)
Not
e:Pa
thog
enn
ames
hav
ebe
enup
date
d.*P
ath
ogen
slis
ted
show
edse
nsi
tivi
tyto
atle
ast
one
fatt
yac
idin
the
com
pari
son
.Pa
thog
ens
that
faile
dto
show
inh
ibit
ion
byei
ther
cate
gory
ofFA
incl
uded
Pseu
dom
onas
aeru
gino
saan
dEs
cher
ichi
aco
li(Z
hen
get
al.
2005
)an
dL
iste
ria
mon
ocyt
ogen
es(R
ein
eret
al.
1986
).
September 2012 205NUTRIENT SIGNALING
TA
BL
E8
Ant
imic
robi
alac
tivity
ofom
ega-
3an
dom
ega-
6po
lyun
satu
rate
dfa
ttyac
ids
Om
ega-
3P
UFA
stud
ied
Ant
imic
robi
alco
mpa
riso
nO
meg
a-6
PU
FAst
udie
dP
atho
gens
inhi
bite
dby
FA*
Are
omeg
a-3
PU
FAm
ore
anti
mic
robi
al?
Ref
eren
ces
C18
:3lin
olen
icC
20:5
C22
:6
�C
18:2
C20
:4C
18:3
gam
ma
linol
enic
Bac
illus
cere
usB
acte
roid
esfr
agili
sB
acte
roid
essp
p.C
lost
ridi
umbo
tulin
umC
lost
ridi
umpe
rfri
ngen
sEs
cher
ichi
aco
liEn
tero
cocc
usfa
ecal
isH
elic
obac
ter
pylo
riG
iard
iala
mbl
iaL
iste
ria
mon
ocyt
ogen
esM
ycop
lasm
abo
vis
Myc
opla
sma
tube
rcul
osis
Salm
onel
laty
phim
uriu
mSt
aphy
loco
ccus
aure
usSt
rept
ococ
cus
spp.
yes
(15)
(Gut
teri
dge
etal
.19
74;
But
cher
etal
.19
76;
Alt
enbe
rn19
77b;
Kon
doan
dK
anai
1977
;H
eczk
oet
al.
1979
;L
acey
and
Lor
d19
81;
Kn
app
and
Mel
ly19
86;
Roh
rer
etal
.19
86;
Hog
anet
al.
1988
;T
hom
pson
etal
.19
90;
Aba
bouc
het
al.
1992
;W
ang
and
Joh
nso
n19
92;
Th
omps
onet
al.
1994
;Pe
tron
eet
al.
1998
;Su
net
al.
2003
)
C18
:3�
C18
:2C
20:4
Can
dida
albi
cans
Gia
rdia
lam
blia
Lis
teri
am
onoc
ytog
enes
Stap
hylo
cocc
usau
reus
Stre
ptoc
occu
sG
roup
ASt
rept
ococ
cus
Gro
upB
no
(7)
(Will
ett
and
Mor
se19
66;
Fulle
ran
dM
oore
1967
;K
abar
aet
al.
1972
;R
aych
owdh
ury
etal
.19
85;
Rei
ner
etal
.19
86;
Mba
ndi
etal
.20
04;
Zh
eng
etal
.20
05)*
*
Not
e:W
hen
the
lipid
num
ber
fails
todi
stin
guis
hbe
twee
nsi
mila
rFA
,co
mm
onn
ames
offa
tty
acid
sar
egi
ven
inpa
ren
thes
es.
Path
ogen
slis
ted
show
edse
nsi
tivi
tyto
atle
ast
one
fatt
yac
idin
the
com
pari
son
.*P
ath
ogen
slis
ted
show
edse
nsi
tivi
tyto
atle
ast
one
fatt
yac
idin
the
com
pari
son
.Pa
thog
ens
that
faile
dto
show
inh
ibit
ion
byei
ther
cate
gory
ofFA
incl
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206 Volume 87THE QUARTERLY REVIEW OF BIOLOGY
ported increased bacterial inhibition byMUFA, and four had mixed results (Table 8).
Although antimicrobial activity generallyincreased with rising numbers of doublebonds (Knapp and Melly 1986), studies re-port less consistent relationships betweenthe number of double bonds and inflam-matory activity of unsaturated FA. MUFAhad stronger proinflammatory effects com-pared to PUFA in 11 studies that we found;nine studies showed the opposite pattern; andone study showed equivalent inflammation(Tables 3 and 5). The outcome of these com-parisons often depended on whether theMUFA oleic acid was compared to the (gen-erally proinflammatory) omega-6 PUFA (Su-riyaphol et al. 2002; Matesanz et al. 2011) orthe (generally anti-inflammatory) omega-3PUFA (Carluccio et al. 1999; Shaw et al.2007).
Independence testing of effects on micro-bial growth and human cell inflammationshowed a borderline-significant statisticaltrend for MUFA versus PUFA of the samechain length (p�0.094, Fisher’s exact test,Table 5).
Comparison 5. Trans versus CisUnsaturated Fatty Acids
Kabara and colleagues found that forgram positive organisms, trans isomers ofC16 and C18 were inactive as antimicrobialagents, whereas replacement of a trans witha cis double bond increased their antimi-crobial activity (Kabara et al. 1972, 1977).These results have since been replicated(Table 9). Trans fats have a similar struc-ture to saturated fats and likewise are oftenineffective in killing gut microbes (Desboisand Smith 2010). Increased antimicrobialactivity of cis FA compared to trans FA was themost frequent observation in pooled lipid-lipid comparisons (Figure 4e). Replacementof all trans double bonds with cis doublebonds made the FA more antimicrobial inseven of eight studies (Table 9). In contrastto the predictions of our model, and con-trary to supplementation trials and observa-tional studies (Mozaffarian 2006), trans FAwere equally likely to be less or more inflam-matory than their cis isomers in our review ofin vitro studies. Although trans FA can show
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September 2012 207NUTRIENT SIGNALING
proinflammatory effects much like long-chain saturated FA (Turpeinen et al. 1998),in the comparison of trans versus cis FA, therelationship between inflammatory effectsand antimicrobial activity was not significant(p�0.28, Fisher’s exact test, Table 5).
DiscussionThe inflammatory effects of foods have gen-
erated much scientific interest, but have lackeda conceptual framework to explain the myriadimmune modulatory effects of specific dietarynutrients. Our model builds from the observa-tion that many of the same nutrients that mod-ulate inflammation have powerful effects onthe survival of harmful gut microorganismsand the ability of pathogens to adhere to epi-thelial cells. Because of these effects, somenutrients are better suited than others to par-ticipate in a coordinated defense with antimi-crobial effector molecules of the host immunesystem (Nakatsuji et al. 2010). Inflammationcaused by nutrients requires mobilization ofscarce host resources (McDade 2003), whilealso potentially contributing to tissue damage(Margioris 2009). The nutrient signaling hy-pothesis proposes that the direct postprandialinflammatory effects of FA are an evolved re-sponse that help the host balance these costs ofimmune activation with the potential benefitof mobilizing these costly resources. Whencommonly encountered nutrients consistentlyalter patterns of gut bacterial growth and in-crease the ability of pathogens or pathobiontsto adhere to the intestinal epithelium, ourmodel predicts that natural selection will havefavored inflammatory signaling that corre-sponds to the change in risk. We find substan-tial support for this hypothesis in previouslypublished research on the antimicrobial effectsof saturated and unsaturated FA. With somenotable exceptions, contrasts of FA that dif-fered in other structural features were also gen-erally in line with the expectations of thismodel (Table 5).
In our primary comparison between sat-urated versus unsaturated FA, lipids thatmet the nutrient needs of pathogens (byproviding a source of carbon) tended to havedirect proinflammatory effects on the host; incontrast, lipids that impaired the growth ofharmful pathogens tended to attenuate inflam-
mation in human cells (Table 5). Similarassociations between antimicrobial and an-ti-inflammatory effects were found for thecontrasts involving omega-3 FA and for theeffects of increasing chain length in satu-rated FA (Table 5). We found less consis-tent support for our hypothesis in severalcomparisons that examined other struc-tural differences between unsaturated FA.For example, monounsaturated fats werenot found to clearly serve a proinflamma-tory signaling role compared to PUFA (Table5). These equivocal results are in line withuncertainty about whether increased con-sumption of MUFA decreases or increasescardiovascular risk and diabetes (Micha andMozaffarian 2010). On the other hand, con-sumption of trans fats from industrial sourceshas been shown to increase the risk of heartdisease (Mozaffarian 2006; Kummerow 2009).Despite strong epidemiologic evidence linkingtrans fats to diseases, we did not find consistentevidence for a direct proinflammatory signal-ing role of trans fats on human cells (Table5). One possible explanation for our inabil-ity to demonstrate a significant association ofthe effects of trans versus cis FA on microbesand inflammation is simply the small sampleof studies available to test it. Alternatively,our findings may reflect the fact that transfats are often manufactured as hydrogenatedvegetable oils and comprised a trivial frac-tion of the preindustrial diet (Cordain et al.2005), and thus would not have exertedstrong selection pressure on the human im-mune system until the past few generations.
An important limitation of our approachis that the studies we reviewed evaluated FAeffects on a narrow spectrum of gut microbes,mostly pathogens such as Staphylococcus aureusand Listeria monocytogenes (Batovska et al. 2009).These pathogenic microorganisms comprisea small minority of the gut microbiota (Wuet al. 2011). Compared to specialized patho-gens, the potentially harmful commensalsknown as pathobionts are quantitativelymore numerous and persistent in the micro-biome (Lee and Mazmanian 2010). Becauseof these features, Lee and Mazmanian (2010)have suggested that pathobionts are more im-portant than pathogens in shaping the evolu-tion of immune responses. If this proposal is
208 Volume 87THE QUARTERLY REVIEW OF BIOLOGY
true, then FA inhibition of pathobionts, such asBacteroides fragilis (Gutteridge et al. 1974;Thompson et al. 1990), may have a dispropor-tionate selective impact on nutrient-related in-flammation. However, FA have similar effectson bacteria from both groups (e.g., Table 7)and nutrient-induced immune responses maycompensate for the adverse effects of increasednumbers of either pathogens or pathobiontson the host’s resistance to infection.
Because the studies that we review docu-ment microbial effects of FA in vitro, it is notcertain how these in vitro effects manifest invivo, and whether the concentrations of FAavailable in the diet can affect the growth ofbacteria in the gut. However, some studies sug-gest that concentrations of lipids present in thegastrointestinal tract are sufficient to influencebacterial growth (Shin et al. 2002; Sun et al.2007). For example, hydrolysis of milk fat bylipases yields FA and monoglycerides in milli-molar (mM) concentrations in the stomach(3.35 mM and 12 mM) that are effective inkilling bacteria such as Helicobacter pylori (Sun etal. 2007). In the small intestine, the site ofabsorption of most dietary FA, triglyceridesand free FA also have been measured in milli-molar concentrations in the postprandial state(Di Maio and Carrier 2011); similar concentra-tions are bactericidal to a variety of gut patho-gens (Sprong et al. 2001). In the human colon,the concentration of shorter-chain FA havebeen measured in the millimolar range (e.g.,124 mM; Bergman 1990) and that has beenshown to inhibit the growth of bacteria suchas E. coli O157:H7 (Shin et al. 2002). Al-though the effects of inhibitory FA andmonoglycerides on bacterial growth are addi-tive (Sun et al. 2003), many FA have synergisticeffects against pathogens with other elementsof the innate immune system, including anti-microbial peptides (Nakatsuji et al. 2010), lac-toferrin and lysozyme (Ellison and Giehl 1991;Martinez et al. 2009), and gastric acid (Berg-sson et al. 2002; Thormar et al. 2006). Theamplification of antipathogen activity by hostfactors suggests that some FA, even at concen-trations in which they are inactive in isolation,may have the ability to modify the gut micro-biota in vivo and thus alter infectious risk.
Despite the limitations described above,our model holds promise to help explain
why the host immune system has evolved acapacity to modulate inflammation in re-sponse to dietary fats. The parallels betweenthe effects of many lipids on pathogens andon host immunity (Table 5) are consistentwith our hypothesis that the lipid effects ongut microorganisms have shaped the verte-brate immune system to modify expenditureon costly host defenses in ways that are appro-priate in light of impending changes in gutbiota predicted by the pattern of ingested nu-trients. Anti-inflammatory signaling from anti-microbial nutrients reduces the energetic costsand tissue damage associated with inflamma-tion, while potentially also sparing protectivecommensal gut organisms. Meanwhile, ourmodel argues that inflammation from promi-crobial nutrients, while costly, provides a ben-efit to host defense by improving resistance toinfection at the intestinal epithelial barrier.
Evolutionary Symbiosis in ImmuneDefense
Several recent papers have presentedmodels of immune defense that share sim-ilarities with the nutrient signaling modeloutlined here. These studies point to theplausibility of the general framework thatwe review, and also highlight differences inthe predictions of the various models thathave been presented. In several elegantexperiments, Nakatsuji et al. (2010) andChen et al. (2011) have shown how innateimmune defense of the skin relies on FA,symbiotic bacteria, and host antimicrobialpeptides to prevent infection by pathogens.These researchers have shown that FA on theskin work in concert with antimicrobial pep-tides to maintain a protective antimicrobialenvironment. Various FA stimulate the pro-duction of skin defensins that function to-gether to prevent overgrowth by the skincommensal Propionibacterium acnes (Nakatsujiet al. 2010). These findings highlight the abilityof FA to provide an important adjunct to theantimicrobial molecules of the innate immunesystem. Coordinated innate defense involvingnutrient FA and antimicrobial products of theimmune system occurs throughout the gastro-intestinal tract (Figure 5). However, the nutri-ent signaling model differs in one critical wayfrom the viewpoint offered by these authors.
September 2012 209NUTRIENT SIGNALING
Nakatsuji et al. (2010) suggest that the ben-efit of antimicrobial FA relies on the abilityof these FA to stimulate the host to increasethe production of immune products (e.g.,antimicrobial peptides) that participate in acoordinated antimicrobial defense. The nu-trient signaling model predicts the opposite:that exogenous FA with intrinsic antimicro-bial properties allows the host to decrease itsinvestment in antimicrobial defenses. In fact,findings of Nakatsuji and colleagues suggestthat skin FA with the least intrinsic antimi-crobial activity against P. acnes (oleic acid andpalmitic acid) are the FA that stimulate thegreatest production of antimicrobial pep-tides by the host. The FA with the greatestantimicrobial activity against P. acnes (lauricacid) showed the least ability to upregulatedefensin production by epithelial cells.These results are in line with expectations ofthe nutrient signaling model.
Nutrient Signaling versus thePaleolithic Diet
It has been suggested previously that hu-man metabolism was adapted to the dietand lifestyle of nomadic foragers duringseveral million years of hominin evolution(Neel 1962; Eaton et al. 1988). According to
this framework, rapid changes in diet in recentgenerations have led to a “discordance” or“mismatch” between a modern diet and theancestral diet that our metabolisms haveevolved to expect. Many nutrients that arecommonly consumed today were rare or ab-sent in past environments. Processed foodsand refined sugars that dominate the typicalWestern diet represent a radical transforma-tion from the diet of humans and homininsduring the Paleolithic era (2.6 million to10,000 years ago) (Cordain et al. 2005). Transfats have been introduced in great quantitiesinto the food supply by the industrial hydroge-nation of vegetable oils (Cordain et al. 2005).Modern agricultural practices have also al-lowed the harvesting of meat with a muchhigher concentration of saturated FA thanwild game, in which much edible carcass fatconsists of monounsaturated fat or PUFA(Cordain et al. 2005). In addition, the omega-3FA content is higher in wild fish and gamethan in farmed meat. As a result, ancestral hu-man populations likely consumed omega-3 FAin much higher proportion to omega-6 FAcompared to today (Teitelbaum and Walker2001). It has been suggested that the de-creased ratio of omega-3 to omega-6 FA inthe diet, compared to the ancestral humanstate, is a source of increased proinflamma-tory eicosanoid synthesis contributing to theepidemic of diabetes and cardiovascular dis-ease (Teitelbaum and Walker 2001).
Our hypothesis differs fundamentally fromthe Paleolithic diet concept in proposing thatnutrients themselves will only have a direct pro-inflammatory or anti-inflammatory signalingrole if human ancestors commonly encoun-tered them in the past, or if they chemicallymimic nutrients that were commonly encoun-tered. The immune system would haveevolved a capacity to mobilize nonspecificimmune defenses, notably inflammation, inresponse to commonly encountered nutri-ents (those ingested or transformed by bac-teria) that had adverse effects on the gutmicrobiota. Today, exposure to these lipidsshould initiate inflammation, while the im-mune system would not be expected to haveevolved a response to a compound that wasnot consumed by human ancestors, or onlyrarely. In this sense, our model is distinct in
Figure 5. Fatty Acids Participation in InnateImmune Defenses Along theGastrointestinal Tract
Nutrients vary in their capacity to participate ininnate immune defense of the gastrointestinal (GI)tract. Although some FA impair the intestinal barrierfunction, other FA kill microbes and coordinate withantimicrobial defenses of the host throughout the GItract.
210 Volume 87THE QUARTERLY REVIEW OF BIOLOGY
its predictions from most evolutionary mod-els linking disease to gene-diet mismatch sec-ondary to rapid changes in the quantities ortypes of nutrients consumed. That said, weemphasize that the two models are funda-mentally complementary, and lead to distinctpredictions: the Paleolithic diet model predictsthat rapid change in the nutrient compositionof the diet can lead to metabolic dysregulationand disease. The nutrient signaling model pre-dicts that high consumption of nutrients thatwere common in ancestral diets and had pro-microbial effects will contribute to diet-induced inflammation.
Generalizing the Model to OtherNutrient Classes
The nutrient signaling model proposedhere inspires novel hypotheses that aretestable both within and across species,and across different nutrient classes. At abroad level, the model makes three gen-eral predictions: A dietary compound willexert direct effects on inflammatory geneexpression if it has been a feature of anorganism’s environment and influencesthe gut microbiota; the direction of theeffect of a compound, either proinflamma-tory or anti-inflammatory, will depend onwhether it promotes or inhibits the growthor invasiveness of pathogens and patho-bionts at the mucosal interface, either bydirect toxic effects or by promotion ofcompetitor organisms; and the intensity ofthe inflammatory effect of a nutrient ispredicted to depend on the degree towhich it influences the abundance of gutpathogens and pathobionts or impairs thehost’s ability to contain microorganisms tothe gastrointestinal tract. These hypothe-ses apply broadly across different classes ofmicro- and macronutrients that have beencommonly ingested by animals, and pro-vide a rich framework for devising testablehypotheses. Here we consider a few exam-ples of these extensions of the model andits predictions.
Our model not only potentially helpsexplain the inflammatory effects of dietaryfat, but also may be expanded to accountfor the production and modification of lip-ids by intestinal bacteria, which may have
similar effects on pathogen colonizationand thus are well suited to serve as signalsof changes in microbial risk. Indeed, mostSCFA are produced by commensal gut bac-teria, primarily as a result of the fermentationof carbohydrates (Newburg et al. 2005). Theimportance of this source of SCFA is high-lighted by recent studies that document highrates of sepsis and death when fecal SCFA dis-appear (Shimizu et al. 2011), a mortality riskthat can be ameliorated by feeding patientsSCFA precursors (galactooligosaccharides; Shi-mizu et al. 2009). Some saturated, trans, andhydrogenated FA are the products of bacterialmetabolism and many of these FA also haveantimicrobial properties (O’Shea et al. 2012).Thus, the FA milieu of the gut sends signals toinnate immune cells not simply of impendingrisk due to ingestion of dietary FA, but also ofthe current makeup of the gut microbiota (Ta-zoe et al. 2008; Lee et al. 2010). Note that thepredictions of our model are not changed bythe source of FA: regardless of whether theyoriginate in the diet or as a byproduct of insitu microbial metabolism, FA may altergut microbiota and the invasiveness of bac-teria at the intestinal mucosa and thusserve as signals of risk of bacterial infectionand colonization.
If the nutrient signaling model is correct,similar predictions should apply to other nu-trient classes encountered during vertebrateor human evolution and that reliably influ-ence the gut microbiota. In this regard, it isnotable that many secondary plant com-pounds generally follow the expected pat-tern of antimicrobial and anti-inflammatoryeffects. For example, phenolics from rasp-berries and blueberries inhibit the growth ofpathogens such as Salmonella typhimurium andexert anti-inflammatory effects in humans(Puupponen-Pimia et al. 2005). Plant-derivedphenolics also exert strong antimicrobialeffects against oral pathogens, including Por-phyromonas gingivalis; these compounds also in-hibit the enzyme cyclooxygenase with stronganti-inflammatory effects (Sreenivasan andGaffar 2008). The same pattern applies to res-veratrol in red wine (Boban et al. 2010) and toantimicrobial spices used in many cuisines(Choi et al. 2011). Commonly used spices havebroad-spectrum antimicrobial effects, and
September 2012 211NUTRIENT SIGNALING
their use by humans coincides with increasedrisk of bacterial contamination of food (Billingand Sherman 1998). Many spices and pheno-lics, particularly curcumin, directly inhibitNF-�B proinflammatory signaling in adi-pocytes, macrophages, and muscle cells (Ag-garwal 2010).
In addition, carbohydrates are good can-didates for nutrient signaling. Simple sug-ars, such as glucose and sucrose, increasethe survival of pathogens in an acidic envi-ronment such as that represented by thegut (Goepfert and Hicks 1969). Overcon-sumption of simple sugars results in prolif-eration of gut bacteria and the appearanceof bacterial products in blood (Bergheimet al. 2008). Like long-chain saturated fats,simple sugars can directly stimulate an in-flammatory response (Brown et al. 2008).Other carbohydrates, particularly oligosac-charides (dietary fiber) and glycans, inter-fere with pathogen binding to intestinalepithelial cells. Human milk oligosaccha-rides have been shown to interfere with theadherence of E. coli, Vibrio cholerae, and Sal-monella to human colonocytes (Coppa et al.2006) and can reduce bacterial toxin pro-duction (Newburg 2009). Pectin oligosac-charides can have similar beneficial effects inpreventing colonization of Campylobacter (Ga-nan et al. 2010) and galactooligosaccharidesreduce the epithelial adherence of E. coli andother pathogens (Shoaf et al. 2006; Quinteroet al. 2011). Other oligosaccharides exertdirect bactericidal effects on Staphylococcusaureus and E. coli (Fernandes et al. 2008).Oligosaccharides are also the precursors ofSCFA production in the human colon bybacterial fermentation. These fermentationproducts lower intestinal pH, inhibiting thegrowth of pathogenic species (Newburg etal. 2005). Oligosaccharides also stimulatethe growth of beneficial commensals such asBifidobacterium and competitively displacepathogens (Kapiki et al. 2007). Human milkoligosaccharides are the primary nutrientsubstrate for beneficial Lactobacillus and Bifi-dobacterium species that have a proctectivefunction by producing antibacterial peptides(Fakhry et al. 2009). The antibiotic-like sub-stances (bacteriocins) produced by com-mensal Lactobacillus in the small intestine
have activity against a wide variety of entericpathogens, including E. coli, Shigella sonnei,and Salmonella typhimurium (Fakhry et al.2009; O’Shea et al. 2012). In light of theantipathogen effects of oligosaccharidesand their ability to promote the growth ofbeneficial commensals, our model suggeststhat it is no coincidence that oligosaccha-rides have direct anti-inflammatory effectssimilar to those initiated by “healthy” fats(Bode et al. 2004). The nutrient signalingmodel is eminently testable, and may beapplied to any class of nutrient that hasbeen common in the human diet and thatinfluences gut microbiota.
Although the hypothesis can be general-ized to other nutrients, cross-species differ-ences provide important test cases of themodel and its predictions. In species withlong evolutionary histories of reliance uponnarrow diets, the absence of nutrient vari-ability should be associated with little or nodiet-induced variation in gut flora. Such spe-cies are thus predicted to exhibit reducedimmune sensitivity to nutrients. Parasitic spe-cies, whose diet is limited to nutrients de-rived from its host, provide an example of anorganism with a constrained diet. For exam-ple, lampreys and vampire bats that consumeblood exclusively are expected to show littledirect nutrient-induced inflammationcompared to taxonomically related non-parasitic species that rely upon a more di-verse and variable diet. We imagine thatecologists and nutritionists will be able todevise a wide range of innovative tests ofthe model that we propose here.
Public Health and ClinicalImplications
The nutrient signaling model has impor-tant implications for the treatment andprevention of diseases that involve chronic,low-grade inflammation. Although we havefocused narrowly on testing a hypothesisfor the evolutionary function of diet-basedinflammatory modulation, it is importantto note that inflammation is itself also atrigger of metabolic disturbances (such asinsulin resistance) that are independentrisk factors for many common diseasessuch as diabetes and cardiovascular disease
212 Volume 87THE QUARTERLY REVIEW OF BIOLOGY
(Fernandez-Real and Ricart 2003). Thus,our model could help explain not only thebody’s inflammatory responses to specificnutrients, but could also shed light ondownstream physiologic and health im-pacts of diet-induced inflammation. Themodel proposed here leads to a testableframework to refine our understanding ofthe health impacts of specific nutrients andfood types. Screening of foods for effectson the gut microbiota and on intestinalbarrier function may reveal new roles forgut microorganisms in the pathogenesis ofchronic degenerative diseases and couldalso point to new antimicrobial treatmentstrategies. Improved understanding of themechanisms by which specific nutrients arerecognized and used to induce changes in in-flammation could provide rich targets forpharmaceutical development and drug discov-ery. Ultimately, if validated, this model holdspromise to bring order to a large and impor-tant domain of nutrition research aimed atidentifying helpful nutrients and related phar-maceuticals.
Although the literature that we review pro-vides preliminary support for the model that
we outline, diet can influence health viamany pathways. A direct inflammatory effectof nutrients is only one such effect, and onlypart of the inflammatory burden is attribut-able to diet. Proinflammatory risk factors forchronic inflammatory diseases also includefactors such as excess accumulation of ab-dominal fat (McDade et al. 2009), cigarettesmoking (Ridker and Silvertown 2008), andexposure to bacterial endotoxin (Cani andDelzenne 2009). Our model potentially com-plements current understanding of diseasesthat involve chronic low-level inflammationby helping explain inflammation that is di-rectly induced by dietary fats and otherimmune-modulating nutrients.
acknowledgments
We would like to thank the many individuals whogenerously provided critiques, references, and con-structive feedback on various versions of this manu-script: Jonathan Kabara, John Alcock, Caleb Finch,Paul Sherman, Roland Cooper, Satkirin Khalsa,Henry Lin, Cameron Crandall, Dan Tandberg, andRobert Miller. We also thank the editor and two anon-ymous reviewers whose thoughtful comments andcriticism also helped improve this manuscript.
REFERENCES
Ababouch L., Chaibi A., Busta F. F. 1992. Inhibitionof bacterial spore growth by fatty acids and theirsodium salts. Journal of Food Protection 55:980–984.
Aggarwal B. B. 2010. Targeting inflammation-inducedobesity and metabolic diseases by curcumin andother nutraceuticals. Annual Review of Nutrition 30:173–199.
Ahn D.-H., Crawley S. C., Hokari R., Kato S., YangS. C., Li J.-D., Kim Y. S. 2005. TNF-alpha activatesMUC2 transcription via NF-kappaB but inhibits viaJNK activation. Cellular Physiology and Biochemistry:International Journal of Experimental Cellular Physiol-ogy, Biochemistry and Pharmacology 15:29–40.
Altenbern R. A. 1977a. Cerulenin-inhibited cells ofStaphylococcus aureus resume growth when supple-mented with either a saturated or an unsaturatedfatty acid. Antimicrobial Agents and Chemotherapy 11:574–576.
Altenbern R. A. 1977b. Effects of exogenous fattyacids on growth and enterotoxin B formation byStaphylococcus aureus 14458 and its membrane mu-tant. Canadian Journal of Microbiology 23:389–397.
Altieri C., Bevilacqua A., Cardillo D., Sinigaglia M. 2009.Effectiveness of fatty acids and their monoglycerides
against gram-negative pathogens. International Jour-nal of Food Science and Technology 44:359–366.
Alzoghaibi M. A., Walsh S. W., Willey A., Fowler A. A.,III, Graham M. F. 2003. Linoleic acid, but not oleicacid, upregulates the production of interleukin-8 byhuman intestinal smooth muscle cells isolated frompatients with Crohn’s disease. Clinical Nutrition 22:529–535.
Andersen A. D., Mølbak L., Michaelsen K. F., Laurit-zen L. 2011. Molecular fingerprints of the humanfecal microbiota from 9 to 18 months old and theeffect of fish oil supplementation. Journal of Pedi-atric Gastroenterology and Nutrition 53:303–309.
Badwey J. A., Curnutte J. T., Robinson J. M., BerdeC. B., Karnovsky M. J., Karnovsky M. L. 1984. Ef-fects of free fatty acids on release of superoxideand on change of shape by human neutrophils.Reversibility by albumin. Journal of Biological Chem-istry 259:7870–7877.
Baldie G., Kaimakamis D., Rotondo D. 1993. Fattyacid modulation of cytokine release from humanmonocytic cells. Biochimica et Biophysica Acta 1179:125–133.
Batovska D. I., Todorova I. T., Tsvetkova I. V., Najden-
September 2012 213NUTRIENT SIGNALING
ski H. M. 2009. Antibacterial study of the mediumchain fatty acids and their 1-monoglycerides: indi-vidual effects and synergistic relationships. PolishJournal of Microbiology 58:43–47.
Bergheim I., Weber S., Vos M., Krämer S., Volynets V.,Kaserouni S., McClain C. J., Bischoff S. C. 2008.Antibiotics protect against fructose-induced he-patic lipid accumulation in mice: role of endo-toxin. Journal of Hepatology 48:983–992.
Bergman E. N. 1990. Energy contributions of volatilefatty acids from the gastrointestinal tract in variousspecies. Physiological Reviews 70:567–590.
Bergsson G., Arnfinnsson J., Steingrımsson O., Thor-mar H. 2001. Killing of gram-positive cocci by fattyacids and monoglycerides. APMIS: Acta Patho-logica, Microbiologica et Immunologica Scandinavica109:670–678.
Bergsson G., Steingrımsson O., Thormar H. 2002.Bactericidal effects of fatty acids and monoglycer-ides on Helicobacter pylori. International Journal ofAntimicrobial Agents 20:258–262.
Bergstrom K. S. B., Kissoon-Singh V., Gibson D. L.,Ma C., Montero M., Sham H. P., Ryz N., Huang T.,Velcich A., Finlay B. B., Chadee K., Vallance B. A.2010. Muc2 protects against lethal infectious coli-tis by disassociating pathogenic and commensalbacteria from the colonic mucosa. PLoS Pathogens6(5):e1000902.
Beuchat L. R. 1980. Comparison of anti-Vibrio activ-ities of potassium sorbate, sodium benzoate, andglycerol and sucrose esters of fatty acids. Appliedand Environmental Microbiology 39:1178–1182.
Billing J., Sherman P. W. 1998. Antimicrobial func-tions of spices: why some like it hot. QuarterlyReview of Biology 73:3–49.
Boban N., Tonkic M., Budimir D., Modun D., SutlovicD., Punda-Polic V., Boban M. 2010. Antimicrobialeffects of wine: separating the role of polyphenols,pH, ethanol, and other wine components. Journalof Food Science 75:M322–M326.
Bode L., Kunz C., Muhly-Reinholz M., Mayer K., See-ger W., Rudloff S. 2004. Inhibition of monocyte,lymphocyte, and neutrophil adhesion to endothe-lial cells by human milk oligosaccharides. Throm-bosis and Haemostasis 92:1402–1410.
Brown C. M., Dulloo A. G., Montani J.-P. 2008. Sugarydrinks in the pathogenesis of obesity and cardio-vascular diseases. International Journal of Obesity32(Supplement 6):S28–S34.
Butcher G. W., King G., Dyke K. G. H. 1976. Sensitivityof Staphylococcus aureus to unsaturated fatty acids.Journal of General Microbiology 94:290–296.
Calder P. C. 2002. Dietary modification of inflamma-tion with lipids. Proceedings of the Nutrition Society61:345–358.
Campbell I. M., Crozier D. N., Pawagi A. B., BuividsI. A. 1983. In vitro response of Staphylococcus aureus
from cystic fibrosis patients to combinations oflinoleic and oleic acids added to nutrient me-dium. Journal of Clinical Microbiology 18:408–415.
Canas-Rodriguez A., Smith H. W. 1966. The identifi-cation of the antimicrobial factors of the stomachcontents of sucking rabbits. Biochemical Journal100:79–82.
Cani P. D., Delzenne N. M. 2009. The role of thegut microbiota in energy metabolism and meta-bolic disease. Current Pharmaceutical Design 15:1546–1558.
Carluccio M. A., Massaro M., Bonfrate C., Siculella L.,Maffia M., Nicolardi G., Distante A., Storelli C., DeCaterina R. 1999. Oleic acid inhibits endothelialactivation: a direct vascular antiatherogenic mech-anism of a nutritional component in the mediter-ranean diet. Arteriosclerosis, Thrombosis, and VascularBiology 19:220–228.
Carson D. D., Daneo-Moore L. 1980. Effects of fattyacids on lysis of Streptococcus faecalis. Journal of Bac-teriology 141:1122–1126.
Cavaglieri C. R., Nishiyama A., Fernandes L. C., CuriR., Miles E. A., Calder P. C. 2003. Differentialeffects of short-chain fatty acids on proliferationand production of pro- and anti-inflammatory cy-tokines by cultured lymphocytes. Life Sciences 73:1683–1690.
Chen C.-H., Wang Y., Nakatsuji T., Liu Y.-T., Zoubou-lis C. C., Gallo R. L., Zhang L., Hsieh M.-F., HuangC.-M. 2011. An innate bactericidal oleic acid effec-tive against skin infection of methicillin-resistantStaphylococcus aureus: a therapy concordant withevolutionary medicine. Journal of Microbiology andBiotechnology 21:391–399.
Chene G., Dubourdeau M., Balard P., Escoubet-Lozach L., Orfila C., Berry A., Bernad J., AriesM. F., Charveron M., Pipy B. 2007. n-3 and n-6polyunsaturated fatty acids induce the expressionof COX-2 via PPARgamma activation in humankeratinocyte HaCaT cells. Biochimica et BiophysicaActa 1771:576–589.
Chiou R. Y.-Y, Phillips R. D., Zhao P., Doyle M. P.,Beuchat L. R. 2004. Ethanol-mediated variationsin cellular fatty acid composition and protein pro-files of two genotypically different strains of Esch-erichia coli O157:H7. Applied and EnvironmentalMicrobiology 70:2204–2210.
Choi S.-E., Kim T. H., Yi S.-A., Hwang Y. C., HwangW. S., Choe S. J., Han S. J., Kim H. J., Kim D. J.,Kang Y., Lee K.-W. 2011. Capsaicin attenuates palmi-tate-induced expression of macrophage inflammatoryprotein 1 and interleukin 8 by increasing palmitateoxidation and reducing c-Jun activation in THP-1 (hu-man acute monocytic leukemia cell) cells. NutritionResearch 31:468–478.
Chu A. J., Moore J. 1991. Differential effects of unsat-urated fatty acids on modulation of endotoxin-
214 Volume 87THE QUARTERLY REVIEW OF BIOLOGY
induced tissue factor activation in cultured humanleukemia U937 cells. Cell Biochemistry and Function9:231–238.
Ciccia F., Bombardieri M., Rizzo A., Principato A., GiardinaA. R., Raiata F., Peralta S., Ferrante A., Drago S., Cot-tone M., Pitzalis C., Triolo G. 2010. Over-expression ofpaneth cell-derived anti-microbial peptides in the gutof patients with ankylosing spondylitis and subclinicalintestinal inflammation. Rheumatology 49:2076–2083.
Collie-Duguid E. S. R.,Wahle K.W. J. 1996. Inhibitoryeffect of fish oil N-3 polyunsaturated fatty acids onthe expression of endothelial cell adhesion mole-cules. Biochemical and Biophysical Research Communi-cations 220:969–974.
Coppa G. V., Zampini L., Galeazzi T., Facinelli B., FerranteL., Capretti R., Orazio G. 2006. Human milk oligosac-charides inhibit the adhesion to Caco-2 cells of diar-rheal pathogens: Escherichia coli, Vibrio cholerae,and Salmonella fyris. Pediatric Research 59:377–382.
Cordain L., Eaton S. B., Sebastian A., Mann N.,Lindeberg S., Watkins B. A., O’Keefe J. H., Brand-Miller J. 2005. Origins and evolution of the West-ern diet: health implications for the 21st century.American Journal of Clinical Nutrition 81:341–354.
Cox A. B., Rawlinson L.-A., Baird A. W., Bzik V.,Brayden D. J. 2008. In vitro interactions betweenthe oral absorption promoter, sodium caprate(C10) and S. typhimurium in rat intestinal ilealmucosae. Pharmaceutical Research 25:114–122.
Crouch A. A., Seow W. K., Whitman L. M., ThongY. H. 1991. Effect of human milk and infant milkformulae on adherence of Giardia intestinalis.Transactions of the Royal Society of Tropical Medicineand Hygiene 85:617–619.
Crutchley D. J. 1985. Hydroxyeicosatetraenoic acidsand other unsaturated fatty acids inhibit endotoxin-induced thromboplastin activity in human monocytes.Biochemical and Biophysical Research Communications132:67–73.
Das U. N. 2010. A defect in �6 and �5 desaturases maybe a factor in the initiation and progression ofinsulin resistance, the metabolic syndrome andischemic heart disease in South Asians. Lipids inHealth and Disease 9:130.
De Caterina R., Libby P. 1996. Control of endothelialleukocyte adhesion molecules by fatty acids. Lipids31:S57–S63.
De Caterina R., Bernini W., Carluccio M. A., LiaoJ. K., Libby P. 1998. Structural requirements forinhibition of cytokine-induced endothelial activa-tion by unsaturated fatty acids. Journal of LipidResearch 39:1062–1070.
Di Maio S., Carrier R. L. 2011. Gastrointestinal con-tents in fasted state and post-lipid ingestion: invivo measurements and in vitro models for study-ing oral drug delivery. Journal of Controlled Release151:110–122.
Desbois A. P., Smith V. J. 2010. Antibacterial free fattyacids: activities, mechanisms of action and bio-technological potential. Applied Microbiology andBiotechnology 85:1629–1642.
Desbois A. P., Lebl T., Yan L., Smith V. J. 2008. Iso-lation and structural characterisation of two anti-bacterial free fatty acids from the marine diatom,Phaeodactylum tricornutum. Applied Microbiology andBiotechnology 81:755–764.
Dilika F., Bremner P. D., Meyer J. J. M. 2000. Antibac-terial activity of linoleic and oleic acids isolatedfrom Helichrysum pedunculatum: a plant used dur-ing circumcision rites. Fitoterapia 71:450–452.
Do T. Q., Moshkani S., Castillo P., Anunta S., Pogo-syan A., Cheung A., Marbois B., Faull K. F., ErnstW., Chiang S. M., Fujii G., Clarke C. F., Foster K.,Porter E. 2008. Lipids including cholesteryl lino-leate and cholesteryl arachidonate contribute tothe inherent antibacterial activity of human nasalfluid. Journal of Immunology 181:4177–4187.
Dye E. S., Kapral F. A. 1981. Characterization of abactericidal lipid developing within staphylococ-cal abscesses. Infection and Immunity 32:98–104.
Eaton S. B., Konner M., Shostak M. 1988. Stone agersin the fast lane: chronic degenerative diseases inevolutionary perspective. American Journal of Medi-cine 84:739–749.
Einvik G., Klemsdal T. O., Sandvik L., Hjerkinn E. M.2010. A randomized clinical trial on n -3 polyunsat-urated fatty acids supplementation and all-causemortality in elderly men at high cardiovascular risk.European Journal of Cardiovascular Prevention and Re-habilitation 17:588–592.
Ellison R. T., Giehl T. J. 1991. Killing of gram-negativebacteria by lactoferrin and lysozyme. Journal ofClinical Investigation 88:1080–1091.
Esposito K., Giugliano D. 2006. Diet and inflamma-tion: a link to metabolic and cardiovascular dis-eases. European Heart Journal 27:15–20.
Fakhry S., Manzo N., D’Apuzzo E., Pietrini L., Sorren-tini I., Ricca E., De Felice M., Baccigalupi L. 2009.Characterization of intestinal bacteria tightly bound tothe human ileal epithelium. Research in Microbiology 160:817–823.
Fay J. P., Farias R. N. 1975. The inhibitory action offatty acids on the growth of Escherichia coli. Journalof General Microbiology 91:233–240.
Feldman M., Friedman L. S., Brandt L. J. 2010. Chap-ters 51, 105, 107–110 in Sleisenger and Fordtran’sGastrointestinal and Liver Disease: Pathophysiology, Di-agnosis, Management. Ninth edition. Philadelphia(PA): Elsevier.
Fernandes J. C., Tavaria F. K., Soares J. C., RamosO. S., Joao Monteiro M., Pintado M. E., XavierMalcata F. 2008. Antimicrobial effects of chitosansand chitooligosaccharides, upon Staphylococcus au-
September 2012 215NUTRIENT SIGNALING
reus and Escherichia coli, in food model systems.Food Microbiology 25:922–928.
Fernandez-Real J. M., Ricart W. 2003. Insulin resis-tance and chronic cardiovascular inflammatorysyndrome. Endocrine Reviews 24:278–301.
Finch C. E. 2007. The Biology of Human Longevity: In-flammation, Nutrition, and Aging in the Evolution ofLife Spans. Burlington (MA): Academic Press.
Fuller R., Moore J. H. 1967. The inhibition of thegrowth of Clostridium welchii by lipids isolated fromthe contents of the small intestine of the pig.Journal of General Microbiology 46:23–41.
Galbraith H., Miller T. B., Paton A. M., ThompsonJ. K. 1971. Antibacterial activity of long chain fattyacids and the reversal with calcium, magnesium,ergocalciferol and cholesterol. Journal of AppliedBacteriology 34:803–813.
Ganan M., Collins M., Rastall R., Hotchkiss A. T.,Chau H. K., Carrascosa A. V., Martinez-RodriguezA. J. 2010. Inhibition by pectic oligosaccharides ofthe invasion of undifferentiated and differenti-ated Caco-2 cells by Campylobacter jejuni. Interna-tional Journal of Food Microbiology 137:181–185.
Goepfert J. M., Hicks R. 1969. Effect of volatile fattyacids on Salmonella typhimurium. Journal of Bacteri-ology 97:956–958.
Goldman A. S. 2002. Evolution of the mammary glanddefense system and the ontogeny of the immunesystem. Journal of Mammary Gland Biology and Neo-plasia 7:277–289.
Goua M., Mulgrew S., Frank J., Rees D., SneddonA. A., Wahle K. W. J. 2008. Regulation of adhesionmolecule expression in human endothelial andsmooth muscle cells by omega-3 fatty acids andconjugated linoleic acids: involvement of the tran-scription factor NF-�B? Prostaglandins, Leukotrienesand Essential Fatty Acids 78:33–43.
Greenway D. L. A., Dyke K. G. H. 1979. Mechanism ofthe inhibitory action of linoleic acid on the growthof Staphylococcus aureus. Journal of General Microbiol-ogy 115:233–245.
Gutteridge J. M. C., Lamport P., Dormandy T. L.1974. Autoxidation as a cause of antibacterial ac-tivity in unsaturated fatty acids. Journal of MedicalMicrobiology 7:387–389.
Hamer H. M., Jonkers D., Venema K., Vanhoutvin S.,Troost F. J., Brummer R.-J. 2008. Review article:the role of butyrate on colonic function. Alimen-tary Pharmacology & Therapeutics 27:104–119.
Hamosh M., Peterson J. A., Henderson T. R., ScallanC. D., Kiwan R., Ceriani R. L., Armand M., MehtaN. R., Hamosh P. 1999. Protective function ofhuman milk: the milk fat globule. Seminars in Peri-natology 23:242–249.
Hanssen S. A., Hasselquist D., Folstad I., Erikstad K. E.2004. Costs of immunity: immune responsivenessreduces survival in a vertebrate. Proceedings of The
Royal Society, Series B: Biological Sciences 271:925–930.
Hardy S. J., Ferrante A., Poulos A., Robinson B. S.,Johnson D. W., Murray A. W. 1994. Effect of ex-ogenous fatty acids with greater than 22 carbonatoms (very long chain fatty acids) on superoxideproduction by human neutrophils. Journal of Im-munology 153:1754–1761.
Harvey K. A., Arnold T., Rasool T., Antalis C., MillerS. J., Siddiqui R. A. 2008. Trans -fatty acids inducepro-inflammatory responses and endothelial celldysfunction. British Journal of Nutrition 99:723–731.
Harvey K. A., Walker C. L., Pavlina T. M., Xu Z.,Zaloga G. P., Siddiqui R. A. 2010a. Long-chainsaturated fatty acids induce pro-inflammatory re-sponses and impact endothelial cell growth. Clin-ical Nutrition 29:492–500.
Harvey K. A., Walker C. L., Xu Z., Whitley P., PavlinaT. M., Hise M., Zaloga G. P., Siddiqui R. A. 2010b.Oleic acid inhibits stearic acid-induced inhibitionof cell growth and pro-inflammatory responses inhuman aortic endothelial cells. Journal of LipidResearch 51:3470–3480.
Hassinen J. B., Durbin G. T., Bernhart F. W. 1951.The bacteriostatic effects of saturated fatty acids.Archives of Biochemistry 31:183–189.
Håversen L., Danielsson K. N., Fogelstrand L., Wik-lund O. 2009. Induction of proinflammatory cyto-kines by long-chain saturated fatty acids in humanmacrophages. Atherosclerosis 202:382–393.
Heczko P. B., Lutticken R., Hryniewicz W., NeugebauerM., Pulverer G. 1979. Susceptibility of Staphylococcusaureus and group A, B, C, and G Streptococci to freefatty acids. Journal of Clinical Microbiology 9:333–335.
Hogan J. S., Smith K. L., Todhunter D. A., Schoen-berger P. S. 1988. Growth responses of environ-mental mastitis pathogens to long-chain fatty ac-ids. Journal of Dairy Science 71:245–249.
Holzer R. G., Park E.-J., Li N., Tran H., Chen M., ChoiC., Solinas G., Karin M. 2011. Saturated fatty acidsinduce c-Src clustering within membrane sub-domains, leading to JNK activation. Cell 147:173–184.
Horani M. H., Haas M. J., Mooradian A. D. 2006.Saturated, unsaturated, and trans-fatty acids mod-ulate oxidative burst induced by high dextrose inhuman umbilical vein endothelial cells. Nutrition22:123–127.
Hoshimoto A., Suzuki Y., Katsuno T., Nakajima H.,Saito Y. 2002. Caprylic acid and medium-chaintriglycerides inhibit IL-8 gene transcription inCaco-2 cells: comparison with the potent histonedeacetylase inhibitor trichostatin A. British Journalof Pharmacology 136:280–286.
Hu F. B., Stampfer M. J., Manson J. E., Ascherio A.,Colditz G. A., Speizer F. E., Hennekens C. H.,Willett W. C. 1999. Dietary saturated fats and their
216 Volume 87THE QUARTERLY REVIEW OF BIOLOGY
food sources in relation to the risk of coronaryheart disease in women. American Journal of ClinicalNutrition 70:1001–1008.
Huang Z. H., Hii C. S. T., Rathjen D. A., Poulos A.,Murray A. W., Ferrante A. 1997. N-6 and n-3 poly-unsaturated fatty acids stimulate translocation ofprotein kinase C�, -�I, -�II and -� and enhanceagonist-induced NADPH oxidase in macrophages.Biochemical Journal 325:553–557.
Huang C. B., George B., Ebersole J. L. 2010. Antimi-crobial activity of n-6, n-7 and n-9 fatty acids andtheir esters for oral microorganisms. Archives ofOral Biology 55:555–560.
Huang C. B., Alimova Y., Myers T. M., Ebersole J. L.2011. Short- and medium-chain fatty acids exhibitantimicrobial activity for oral microorganisms. Ar-chives of Oral Biology 56:650–654.
Hwang T.-L., Su Y.-C., Chang H.-L., Leu Y.-L., ChungP.-J., Kuo L.-M., Chang Y.-J. 2009. Suppression ofsuperoxide anion and elastase release by C18 un-saturated fatty acids in human neutrophils. Journalof Lipid Research 50:1395–1408.
Isaacs C. E. 2001. The antimicrobial function of milklipids. Advances in Nutritional Research 10:271–285.
Isaacs C. E., Kashyap S., Heird W. C., Thormar H.1990. Antiviral and antibacterial lipids in humanmilk and infant formula feeds. Archives of Disease inChildhood 65:861–864.
Ishiyama J., Taguchi R., Yamamoto A., Murakami K.2010. Palmitic acid enhances lectin-like oxidizedLDL receptor (LOX-1) expression and promotesuptake of oxidized LDL in macrophage cells. Ath-erosclerosis 209:118–124.
Jump D. B. 2004. Fatty acid regulation of gene tran-scription. Critical Reviews in Clinical Laboratory Sci-ences 41:41–78.
Jumpertz R., Le D. S., Turnbaugh P. J., Trinidad C.,Bogardus C., Gordon J. I., Krakoff J. 2011. Energy-balance studies reveal associations between gutmicrobes, caloric load, and nutrient absorption inhumans. American Journal of Clinical Nutrition 94:58–65.
Kabara J. J., Swieczkowski D. M., Conley A. J., TruantJ. P. 1972. Fatty acids and derivatives as antimicro-bial agents. Antimicrobial Agents and Chemotherapy2:23–28.
Kabara J. J., Conley A. J., Swieczkowski D. M., IsmailI. A., Lie Ken Jie M., Gunstone F. D. 1973. Anti-microbial action of isomeric fatty acids on group AStreptococcus. Journal of Medicinal Chemistry 16:1060–1063.
Kabara J. J., Vrable R., Lie Ken Jie M. 1977. Antimi-crobial lipids: natural and synthetic fatty acids andmonoglycerides. Lipids 12:753–759.
Kapiki A., Costalos C., Oikonomidou C., Triantafylli-dou A., Loukatou E., Pertrohilou V. 2007. Theeffect of a fructo-oligosaccharide supplemented
formula on gut flora of preterm infants. Early Hu-man Development 83:335–339.
Kariko K., Rosenbaum H., Kuo A., Zurier R. B., Barna-than E. S. 1995. Stimulatory effect of unsaturated fattyacids on the level of plasminogen activator inhibitor-1mRNA in cultured human endothelial cells. FEBS Let-ters 361:118–122.
Karsten S., Schäfer G., Schauder P. 1994. Cytokineproduction and DNA synthesis by human periph-eral lymphocytes in response to palmitic, stearic,oleic, and linoleic acid. Journal of Cellular Physiology161:15–22.
Keeney K. M., Finlay B. B. 2011. Enteric pathogenexploitation of the microbiota-generated nutrientenvironment of the gut. Current Opinion in Micro-biology 14:92–98.
Kelsey J. A., Bayles K. W., Shafii B., McGuire M. A.2006. Fatty acids and monoacylglycerols inhibitgrowth of Staphylococcus aureus. Lipids 41:951–961.
Kennedy A., Martinez K., Chuang C.-C., LaPoint K.,McIntosh M. 2009. Saturated fatty acid-mediatedinflammation and insulin resistance in adiposetissue: mechanisms of action and implications.Journal of Nutrition 139:1–4.
Keweloh H., Heipieper H. J. 1996. Trans unsaturatedfatty acids in bacteria. Lipids 31:129–137.
Khalfoun B., Thibault F., Watier H., Bardos P., Leb-ranchu Y. 1997. Docosahexaenoic and eicosapen-taenoic acids inhibit in vitro human endothelialcell production of interleukin-6. Advances in Exper-imental Medicine and Biology 400B:589–597.
Khovidhunkit W., Kim M. S., Memon R. A., ShigenagaJ. K., Moser A. H., Feingold K. R., Grunfeld C.2004. Effects of infection and inflammation onlipid and lipoprotein metabolism: mechanismsand consequences to the host. Journal of Lipid Re-search 45:1169–1196.
Khulusi S., Ahmed H. A., Patel P., Mendall M. A.,Northfield T. C. 1995. The effects of unsaturatedfatty acids on Helicobacter pylori in vitro. Journal ofMedical Microbiology 42:276–282.
Kinderlerer J. L., Matthias H. E., Finner P. 1996.Effect of medium-chain fatty acids in mould rip-ened cheese on the growth of Listeria monocytoge-nes. Journal of Dairy Research 63:593–606.
Kitahara T., Koyama N., Matsuda J., Aoyama Y., Hi-rakata Y., Kamihira S., Kohno S., Nakashima M.,Sasaki H. 2004. Antimicrobial activity of saturatedfatty acids and fatty amines against methicillin-resistant Staphylococcus aureus. Biological and Phar-maceutical Bulletin 27:1321–1326.
Kluge A. G. 2004. On total evidence: for the record.Cladistics 20:205–207.
Knapp H. R., Melly M. A. 1986. Bactericidal effects ofpolyunsaturated fatty acids. Journal of Infectious Dis-eases 154:84–94.
Knodler L. A., Vallance B. A., Celli J., Winfree S.,
September 2012 217NUTRIENT SIGNALING
Hansen B., Montero M., Steele-Mortimer O. 2010.Dissemination of invasive Salmonella via bacterial-induced extrusion of mucosal epithelia. Proceed-ings of the National Academy of Sciences of the UnitedStates of America 107:17733–17738.
Ko S. H. L., Heczko P. B., Pulverer G. 1978. Differentialsusceptibility of Propionibacterium acnes, P. granulosumand P. avidum to free fatty acids. Journal of InvestigativeDermatology 71:363–365.
Kodicek E. 1945. The effect of unsaturated fatty acidson Lactobacillus helveticus and other gram-positivemicro-organisms. Biochemical Journal 39:78–85.
Kondo E., Kanai K. 1972. The lethal effect of long-chain fatty acids on mycobacteria. Japanese Journalof Medical Science and Biology 25:1–13.
Kondo E., Kanai K. 1977. The relationship betweenthe chemical structure of fatty acids and theirmycobactericidal activity. Japanese Journal of Medi-cal Science and Biology 30:171–178.
Kopp A., Gross P., Falk W., Bala M., Weigert J.,Buechler C., Neumeier M., Schölmerich J., Schäf-fler A. 2009. Fatty acids as metabolic mediators ininnate immunity. European Journal of Clinical Inves-tigation 39:924–933.
Krogmann A., Staiger K., Haas C., Gommer N., PeterA., Heni M., Machicao F., Häring H.-U., Staiger H.2011. Inflammatory response of human coronaryartery endothelial cells to saturated long-chainfatty acids. Microvascular Research 81:52–59.
Kummerow F. A. 2009. The negative effects of hydro-genated trans fats and what to do about them.Atherosclerosis 205:458–465.
Kummerow F. A., Mahfouz M. M., Zhou Q. 2007.Trans fatty acids in partially hydrogenated soy-bean oil inhibit prostacyclin release by endothelialcells in presence of high level of linoleic acid.Prostaglandins and Other Lipid Mediators 84:138–153.
Lacey R. W., Lord V. L. 1981. Sensitivity of staphylo-cocci to fatty acids: novel inactivation of linolenicacid by serum. Journal of Medical Microbiology 14:41–49.
Laine P. S., Schwartz E. A., Wang Y., Zhang W.-Y.,Karnik S. K., Musi N., Reaven P. D. 2007. Palmiticacid induces IP-10 expression in human macro-phages via NF-�B activation. Biochemical and Bio-physical Research Communications 358:150–155.
Lee Y. K., Mazmanian S. K. 2010. Has the microbiotaplayed a critical role in the evolution of the adap-tive immune system? Science 330:1768–1773.
Lee J.-Y., Kim Y.-S., Shin D.-H. 2002. Antimicrobialsynergistic effect of linolenic acid and monoglyc-eride against Bacillus cereus and Staphylococcus au-reus. Journal of Agricultural and Food Chemistry 50:2193–2199.
Lee J. Y., Zhao L., Hwang D. H. 2010. Modulation ofpattern recognition receptor-mediated inflamma-
tion and risk of chronic diseases by dietary fattyacids. Nutrition Reviews 68:38–61.
Leik C. E., Walsh S. W. 2005. Linoleic acid, but not oleicacid, upregulates production of interleukin-8 by hu-man vascular smooth muscle cells via arachidonic acidmetabolites under conditions of oxidative stress. Jour-nal of the Society for Gynecologic Investigation 12:593–598.
Li Y., Ferrante A., Poulos A., Harvey D. P. 1996. Neutrophiloxygen radical generation. Synergistic responses to tu-mor necrosis factor and mono/polyunsaturated fattyacids. Journal of Clinical Investigation 97:1605–1609.
Lin C.-K., Tsai H.-C., Lin P.-P., Tsen H.-Y., Tsai C.-C.2008. Lactobacillus acidophilus LAP5 able to inhibitthe Salmonella choleraesuis invasion to the humanCaco-2 epithelial cell. Anaerobe 14:251–255.
Lochmiller R. L., Deerenberg C. 2000. Trade-offs inevolutionary immunology: just what is the cost ofimmunity? Oikos 88:87–98.
Margioris A. N. 2009. Fatty acids and postprandialinflammation. Current Opinion in Clinical Nutritionand Metabolic Care 12:129–137.
Marion-Letellier R., Butler M., Dechelotte P., PlayfordR. J., Ghosh S. 2008. Comparison of cytokinemodulation by natural peroxisome proliferator-activated receptor � ligands with synthetic ligandsin intestinal-like Caco-2 cells and human dendriticcells—potential for dietary modulation of peroxi-some proliferator-activated receptor � in intestinalinflammation. American Journal of Clinical Nutrition87:939–948.
Marounek M., Skrivanova E., Rada V. 2003. Suscepti-bility of Escherichia coli to C2-C18 fatty acids. FoliaMicrobiologica 48:731–735.
Martinez J. G., Waldon M., Huang Q., Alvarez S.,Oren A., Sandoval N., Du M., Zhou F., Zenz A.,Lohner K., Desharnais R., Porter E. 2009. Membrane-targeted synergistic activity of docosahexaenoic acidand lysozyme against Pseudomonas aeruginosa. Biochemi-cal Journal 419:193–200.
Massaro M., Habib A., Lubrano L., Del Turco S.,Lazzerini G., Bourcier T., Weksler B. B., De Ca-terina R. 2006. The omega-3 fatty acid docosa-hexaenoate attenuates endothelial cyclooxygenase-2induction through both NADP(H) oxidase and PKC �
inhibition. Proceedings of the National Academy of Sciencesof the United States of America 103:15184–15189.
Matesanz N., Jewhurst V., Trimble E. R., McGinty A.,Owens D., Tomkin G. H., Powell L. A. 2011. Linoleicacid increases monocyte chemotaxis and adhesion tohuman aortic endothelial cells through protein kinaseC- and cyclooxygenase-2-dependent mechanisms. Jour-nal of Nutritional Biochemistry http://dx.doi.org/10.1016/jnutbio.2011.03.202.
Mayer K., Schmidt R., Muhly-Reinholz M., BögeholzT., Gokorsch S., Grimminger F., Seeger W. 2002.In vitro mimicry of essential fatty acid deficiencyin human endothelial cells by TNF � impact of -3
218 Volume 87THE QUARTERLY REVIEW OF BIOLOGY
versus -6 fatty acids. Journal of Lipid Research 43:944–951.
Mbandi E., Brywig M., Shelef L. A. 2004. Antilisterialeffects of free fatty acids and monolaurin in beefemulsions and hot dogs. Food Microbiology 21:815–818.
McCusker M. M., Grant-Kels J. M. 2010. Healing fatsof the skin: the structural and immunologic rolesof the -6 and -3 fatty acids. Clinics in Dermatology28:440–451.
McDade T. W. 2003. Life history theory and the im-mune system: steps toward a human ecologicalimmunology. American Journal of Physical Anthropol-ogy 122(Supplement):100–125.
McDade T. W., Rutherford J. N., Adair L., Kuzawa C.2009. Population differences in associations betweenC-reactive protein concentration and adiposity: com-parison of young adults in the Philippines and theUnited States. American Journal of Clinical Nutrition 89:1237–1245.
Micha R., Mozaffarian D. 2010. Saturated fat andcardiometabolic risk factors, coronary heart dis-ease, stroke, and diabetes: a fresh look at the evi-dence. Lipids 45:893–905.
Miller R. D., Brown K. E., Morse S. A. 1977. Inhibitoryaction of fatty acids on the growth of Neisseriagonorrhoeae. Infection and Immunity 17:303–312.
Miyauchi S., Hirasawa A., Ichimura A., Hara T.,Tsujimoto G. 2010. New frontiers in gut nutrientsensor research: free fatty acid sensing in thegastrointestinal tract. Journal of PharmacologicalSciences 112:19 –24.
Mozaffarian D. 2006. Trans fatty acids—effects onsystemic inflammation and endothelial function.Atherosclerosis Supplements 7:29–32.
Mozaffarian D., Micha R., Wallace S. 2010. Effects oncoronary heart disease of increasing polyunsatu-rated fat in place of saturated fat: a systematicreview and meta-analysis of randomized con-trolled trials. PLoS Medicine 7:e1000252.
Mukherjee S., Vaishnava S., Hooper L. V. 2008. Multi-layered regulation of intestinal antimicrobial de-fense. Cellular and Molecular Life Sciences 65:3019–3027.
Muller J. A., Ross R. P., Sybesma W. F. H., FitzgeraldG. F., Stanton C. 2011. Modification of the tech-nical properties of Lactobacillus johnsonii NCC 533by supplementing the growth medium with unsat-urated fatty acids. Applied and Environmental Micro-biology 77:6889–6898.
Nagao K.,Yanagita T. 2010. Medium-chain fatty acids:functional lipids for the prevention and treatmentof the metabolic syndrome. Pharmacological Re-search 61:208–212.
Naidoo J. 1981. Effect of pH on inhibition of plasmid-carrying cultures of Staphylococcus aureus by lipids.Microbiology 124:173–179.
Nakatsuji T., Kao M. C., Zhang L., Zouboulis C. C.,Gallo R. L., Huang C.-M. 2010. Sebum free fattyacids enhance the innate immune defense of hu-man sebocytes by upregulating �-defensin-2 ex-pression. Journal of Investigative Dermatology 130:985–994.
Nauroth J. M., Liu Y. C., Van Elswyk M., Bell R., HallE. B., Chung G., Arterburn L. M. 2010. Docosa-hexaenoic acid (DHA) and docosapentaenoicacid (DPAn-6) algal oils reduce inflammatory me-diators in human peripheral mononuclear cells invitro and paw edema in vivo. Lipids 45:375–384.
Neel J. V. 1962. Diabetes mellitus: a “thrifty” genotyperendered detrimental by “progress”? American Jour-nal of Human Genetics 14:353–362.
Newburg D. S. 2009. Neonatal protection by an innateimmune system of human milk consisting of oli-gosaccharides and glycans. Journal of Animal Science87(13 Supplement):26–34.
Newburg D. S., Ruiz-Palacios G. M., Morrow A. L.2005. Human milk glycans protect infants againstenteric pathogens. Annual Review of Nutrition 25:37–58.
Nilsson L., Banfi C., Diczfalusy U., Tremoli E., Ham-sten A., Eriksson P. 1998. Unsaturated fatty acidsincrease plasminogen activator inhibitor-1 expres-sion in endothelial cells. Arteriosclerosis, Thrombosis,and Vascular Biology 18:1679–1685.
O’Neil D. A., Porter E. M., Elewaut D., AndersonG. M., Eckmann L., Ganz T., Kagnoff M. F. 1999.Expression and regulation of the human �-defensinshBD-1 and hBD-2 in intestinal epithelium. Journal ofImmunology 163:6718–6724.
O’Shea E. F., Cotter P. D., Stanton C., Ross R. P., HillC. 2012. Production of bioactive substances byintestinal bacteria as a basis for explaining probi-otic mechanisms: bacteriocins and conjugated li-noleic acid. International Journal of Food Microbiology152:189–205.
Oh D. Y., Talukdar S., Bae E. J., Imamura T., Mori-naga H., Fan W., Li P., Lu W. J., Watkins S. M.,Olefsky J. M. 2010. GPR120 is an omega-3 fattyacid receptor mediating potent anti-inflammatoryand insulin-sensitizing effects. Cell 142:687–698.
Peterson M. L., Schlievert P. M. 2006. Glycerol mono-laurate inhibits the effects of gram-positive selectagents on eukaryotic cells. Biochemistry 45:2387–2397.
Petrone G., Conte M. P., Longhi C., Di Santo S.,Superti F., Ammendolia M. G., Valenti P., SegantiL. 1998. Natural milk fatty acids affect survival andinvasiveness of Listeria monocytogenes. Letters in Ap-plied Microbiology 27:362–368.
Petschow B. W., Batema R. P., Ford L. L. 1996. Sus-ceptibility of Helicobacter pylori to bactericidal prop-erties of medium-chain monoglycerides and free
September 2012 219NUTRIENT SIGNALING
fatty acids. Antimicrobial Agents and Chemotherapy40:302–306.
Priebe M. G., Wang H., Weening D., Schepers M.,Preston T., Vonk R. J. 2010. Factors related tocolonic fermentation of nondigestible carbohy-drates of a previous evening meal increase tissueglucose uptake and moderate glucose-associatedinflammation. American Journal of Clinical Nutrition91:90–97.
Puupponen-Pimiä R., Nohynek L., Alakomi H.-L.,Oksman-Caldentey K.-M. 2005. The action ofberry phenolics against human intestinal patho-gens. BioFactors 23:243–251.
Quintero M., Maldonado M., Perez-Munoz M., Jime-nez R., Fangman T., Rupnow J., Wittke A., RussellM., Hutkins R. 2011. Adherence inhibition ofCronobacter sakazakii to intestinal epithelial cells byprebiotic oligosaccharides. Current Microbiology 62:1448–1454.
Ramakers J. D., Mensink R. P., Schaart G., Plat J. 2007.Arachidonic acid but not eicosapentaenoic acid(EPA) and oleic acid activates NF-�B and elevatesICAM-1 expression in Caco-2 cells. Lipids 42:687–698.
Raychowdhury M. K., Goswami R., Chakrabarti P.1985. Effect of unsaturated fatty acids in growthinhibition of some penicillin-resistant and sensi-tive bacteria. Journal of Applied Bacteriology 59:183–188.
Reiner D. S., Wang C.-S., Gillin F. D. 1986. Humanmilk kills Giardia lamblia by generating toxic lipo-lytic products. Journal of Infectious Diseases 154:825–832.
Remig V., Franklin B., Margolis S., Kostas G., Nece T.,Street J. C. 2010. Trans fats in America: a review oftheir use, consumption, health implications, andregulation. Journal of the American Dietetic Associa-tion 110:585–592.
Richard D., Kefi K., Barbe U., Bausero P., Visioli F.2008. Polyunsaturated fatty acids as antioxidants.Pharmacological Research 57:451–455.
Ridker P. M., Silvertown J. D. 2008. Inflammation,C-reactive protein, and atherothrombosis. Journalof Periodontology 79:1544–1551.
Ridker P. M., Hennekens C. H., Buring J. E., Rifai N.2000. C-reactive protein and other markers of in-flammation in the prediction of cardiovasculardisease in women. New England Journal of Medicine342:836–843.
Riordan S. M., McIver C. J., Thomas D. H., Dun-combe V. M., Bolin T. D., Thomas M. C. 1997.Luminal bacteria and small-intestinal permeabil-ity. Scandinavian Journal of Gastroenterology 32:556–563.
Rohrer L., Winterhalter K. H., Eckert J., Köhler P.1986. Killing of Giardia lamblia by human milk is
mediated by unsaturated fatty acids. AntimicrobialAgents and Chemotherapy 30:254–257.
Rothman D., Allen H., Herzog L., Pilapil A., SeilerC. M., Zurier R. B. 1997. Effects of unsaturatedfatty acids on interleukin-1� production by humanmonocytes. Cytokine 9:1008–1012.
Salanitro J. P., Wegener W. S. 1971. Growth of Esche-richia coli on short-chain fatty acids: growth char-acteristics of mutants. Journal of Bacteriology 108:885–892.
Sanadgol N., Mostafaie A., Bahrami G., Mansouri K.,Ghanbari F., Bidmeshkipour A. 2010. Elaidic acidsustains LPS and TNF-� induced ICAM-1 andVCAM-I expression on human bone marrow en-dothelial cells (HBMEC). Clinical Biochemistry 43:968–972.
Schaefer E. J. 2002. Lipoproteins, nutrition, and heartdisease. American Journal of Clinical Nutrition 75:191–212.
Schaefer M. B., Wenzel A., Fischer T., Braun-DullaeusR. C., Renner F., Dietrich H., Schaefer C. A., See-ger W., Mayer K. 2008. Fatty acids differentiallyinfluence phosphatidylinositol 3-kinase signal trans-duction in endothelial cells: impact on adhesion andapoptosis. Atherosclerosis 197:630–637.
Schaeffler A., Gross P., Buettner R., Bollheimer C.,Buechler C., Neumeier M., Kopp A., Schoel-merich J., Falk W. 2009. Fatty acid-induced induc-tion of Toll-like receptor-4/nuclear factor-kappaBpathway in adipocytes links nutritional signallingwith innate immunity. Immunology 126:233–245.
Schmidt J., Kuhlenschmidt M. S. 2008. Microbial ad-hesion of Cryptosporidium parvum: identification ofa colostrum-derived inhibitory lipid. Molecular andBiochemical Parasitology 162:32–39.
Schneider S. M., Fung V. S., Palmblad J., Babior B. M.2001. Activity of the leukocyte NADPH oxidase inwhole neutrophils and cell-free neutrophil prepa-rations stimulated with long-chain polyunsatu-rated fatty acids. Inflammation 25:17–23.
Schwartz E. A., Zhang W.-Y., Karnik S. K., Borwege S.,Anand V. R., Laine P. S., Su Y., Reaven P. D. 2010.Nutrient modification of the innate immune re-sponse: a novel mechanism by which saturatedfatty acids greatly amplify monocyte inflammation.Arteriosclerosis, Thrombosis, and Vascular Biology 30:802–808.
Sekirov I., Russell S. L., Antunes L. C., Finlay B. B.2010. Gut microbiota in health and disease. Phys-iological Reviews 90:859–904.
Serino M., Luche E., Gres S., Baylac A., Berge M.,Cenac C., Waget A., Klopp P., Iacovoni J., KloppC., Mariette J., Bouchez O., Lluch J., Ouarne F.,Monsan P., Valet P., Roques C., Amar J., Bou-loumie A., Theodorou V., Burcelin R. 2011. Met-abolic adaptation to a high-fat diet is associated
220 Volume 87THE QUARTERLY REVIEW OF BIOLOGY
with a change in the gut microbiota. Gut doi:10.1136/gutjnl-2011-301012.
Shaw D. I., Hall W. L., Jeffs N. R., Williams C. M. 2007.Comparative effects of fatty acids on endothelialinflammatory gene expression. European Journal ofNutrition 46:321–328.
Shi H., Kokoeva M. V., Inouye K., Tzameli I., Yin H.,Flier J. S. 2006. TLR4 links innate immunity andfatty acid-induced insulin resistance. Journal ofClinical Investigation 116:3015–3025.
Sherman P. W., Holland E., Sherman J. S. 2008. Al-lergies: their role in cancer prevention. QuarterlyReview of Biology 83:339–362.
Shimizu K., Ogura H., Goto M., Asahara T., NomotoK., Morotomi M., Matsushima A., Tasaki O., FujitaK., Hosotsubo H., Kuwagata Y., Tanaka H.,Shimazu T., Sugimoto H. 2009. Synbiotics de-crease the incidence of septic complications inpatients with severe SIRS: a preliminary report.Digestive Diseases and Sciences 54:1071–1078.
Shimizu K., Ogura H., Hamasaki T., Goto M., TasakiO., Asahara T., Nomoto K., Morotomi M., Matsu-shima A., Kuwagata Y., Sugimoto H. 2011. Alteredgut flora are associated with septic complicationsand death in critically ill patients with systemicinflammatory response syndrome. Digestive Diseasesand Sciences 56:1171–1177.
Shin R., Suzuki M., Morishita Y. 2002. Influence of intesti-nal anaerobes and organic acids on the growth ofenterohaemorrhagic Escherichia coli O157:H7. Journal ofMedical Microbiology 51:201–206.
Shoaf K., Mulvey G. L., Armstrong G. D., HutkinsR. W. 2006. Prebiotic galactooligosaccharides re-duce adherence of enteropathogenic Escherichiacoli to tissue culture cells. Infection and Immunity74:6920–6928.
Siddiqui R. A., Harvey K. A., Ruzmetov N., Miller S. J.,Zaloga G. P. 2009. n-3 fatty acids prevent whereastrans-fatty acids induce vascular inflammation andsudden cardiac death. British Journal of Nutrition102:1811–1819.
Skrivanova E., Marounek M. 2007. Influence of pH onantimicrobial activity of organic acids against rab-bit enteropathogenic strain of Escherichia coli. FoliaMicrobiologica 52:70–72.
Skrivanova E., Savka O. G., Marounek M. 2004. In vitroeffect of C2-C18 fatty acids on Salmonellas. FoliaMicrobiologica 49:199–202.
Skrivanova E., Marounek M., Dlouha G., Kanka J.2005. Susceptibility of Clostridium perfringens toC2-C18 fatty acids. Letters in Applied Microbiology 41:77–81.
Sorci G., Faivre B. 2009. Inflammation and oxidativestress in vertebrate host-parasite systems. Philosoph-ical Transactions of the Royal Society of London, SeriesB: Biological Sciences 364:71–83.
Sperling R. I., Robin J. L., Kylander K. A., Lee T. H.,
Lewis R. A., Austen K. F. 1987. The effects of N-3polyunsaturated fatty acids on the generation ofplatelet-activating factor-acether by human mono-cytes. Journal of Immunology 139:4186–4191.
Sprong R. C., Hulstein M. F., Van der Meer R. 1999.High intake of milk fat inhibits intestinal coloni-zation of Listeria but not of Salmonella in rats.Journal of Nutrition 129:1382–1389.
Sprong R. C., Hulstein M. F. E., Van der Meer R.2001. Bactericidal activities of milk lipids. Antimi-crobial Agents and Chemotherapy 45:1298–1301.
Sreenivasan P. K., Gaffar A. 2008. Antibacterials asanti-inflammatory agents: dual action agents fororal health. Antonie van Leeuwenhoek 93:227–239.
Stachowska E., Dol�egowska B., Olszewska M., Gutowska I.,Chlubek D. 2004. Isomers of trans fatty acids modifythe activity of platelet 12-P lipoxygenase and cyclooxy-genase/thromboxane synthase. Nutrition 20:570–571.
Staiger H., Staiger K., Stefan N., Wahl H. G., Machicao F.,Kellerer M., Häring H.-U. 2004. Palmitate-induced in-terleukin-6 expression in human coronary artery endo-thelial cells. Diabetes 53:3209–3216.
Staiger H., Staiger K., Haas C., Weisser M., MachicaoF., Häring H.-U. 2005. Fatty acid-induced differen-tial regulation of the genes encoding peroxisomeproliferator-activated receptor-� coactivator-1�and -1� in human skeletal muscle cells that havebeen differentiated in vitro. Diabetologia 48:2115–2118.
Stearns S. C. 1992. The Evolution of Life Histories. Ox-ford (United Kingdom): Oxford University Press.
Summers L. K. M., Fielding B. A., Bradshaw H. A., IlicV., Beysen C., Clark M. L., Moore N. R., FraynK. N. 2002. Substituting dietary saturated fat withpolyunsaturated fat changes abdominal fat distri-bution and improves insulin sensitivity. Diabetolo-gia 45:369–377.
Sun C. Q., O’Connor C. J., Roberton A. M. 2002. Theantimicrobial properties of milkfat after partialhydrolysis by calf pregastric lipase. Chemico-Biological In-teractions 140:185–198.
Sun C. Q., O’Connor C. J., Roberton A. M. 2003.Antibacterial actions of fatty acids and monoglyc-erides against Helicobacter pylori. FEMS Immunologyand Medical Microbiology 36:9–17.
Sun C. Q., O’Connor C. J., MacGibbon A. K. H.,Roberton A. M. 2007. The products from lipase-catalysed hydrolysis of bovine milkfat kill Helicobac-ter pylori in vitro. FEMS Immunology and MedicalMicrobiology 49:235–242.
Suriyaphol P., Fenske D., Zähringer U., Han S.-R.,Bhakdi S., Husmann M. 2002. Enzymatically mod-ified nonoxidized low-density lipoprotein inducesinterleukin-8 in human endothelial cells: role offree fatty acids. Circulation 106:2581–2587.
Swann P. G., Parent C. A., Croset M., Fonlupt P.,Lagarde M., Venton D. L., Le Breton G. C. 1990.
September 2012 221NUTRIENT SIGNALING
Enrichment of platelet phospholipids with eicosa-pentaenoic acid and docosahexaenoic acid inhib-its thromboxane A2/prostaglandin H2 receptorbinding and function. Journal of Biological Chemistry265:21692–21697.
Tazoe H., Otomo Y., Kaji I., Tanaka R., Karaki S.-I.,Kuwahara A. 2008. Roles of short-chain fatty acidsreceptors, GPR41 and GPR43 on colonic func-tions. Journal of Physiology and Pharmacology 59(Sup-plement 2):251–262.
Teitelbaum J. E., Walker W. A. 2001. Review: the roleof omega 3 fatty acids in intestinal inflammation.Journal of Nutritional Biochemistry 12:21–32.
Thompson L., Edwards R. E., Greenwood D., SpillerR. C. 1990. Inhibitory effect of long chain fattyacids (LCFAs) on colonic bacteria. Gut 31:A1167.
Thompson L., Cockayne A., Spiller R. C. 1994. Inhib-itory effect of polyunsaturated fatty acids on thegrowth of Helicobacter pylori: a possible explanationof the effect of diet on peptic ulceration. Gut35:1557–1561.
Thormar H., Isaacs C. E., Brown H. R., BarshatzkyM. R., Pessolano T. 1987. Inactivation of envel-oped viruses and killing of cells by fatty acids andmonoglycerides. Antimicrobial Agents and Chemo-therapy 31:27–31.
Thormar H., Hilmarsson H., Bergsson G. 2006. Stableconcentrated emulsions of the 1-monoglyceride ofcapric acid (monocaprin) with microbicidal activ-ities against the food-borne bacteria Campylobacterjejuni, Salmonella spp., and Escherichia coli. Appliedand Environmental Microbiology 72:522–526.
Toborek M., Lee Y. W., Garrido R., Kaiser S., Hennig B.2002. Unsaturated fatty acids selectively induce an in-flammatory environment in human endothelial cells.American Journal of Clinical Nutrition 75:119–125.
Tollin M., Bergsson G., Kai-Larsen Y., Lengqvist J.,Sjövall J., Griffiths W., Skuladottir G. V., Haraldsson A.,Jörnvall H., Gudmundsson G. H., Agerberth B. 2005.Vernix caseosa as a multi-component defence systembased on polypeptides, lipids and their interactions.Cellular and Molecular Life Sciences 62:2390–2399.
Tull S. P., Yates C. M., Maskrey B. H., O’Donnell V. B.,Madden J., Grimble R. F., Calder P. C., Nash G. B.,Rainger G. E. 2009. Omega-3 Fatty acids and inflam-mation: novel interactions reveal a new step in neutro-phil recruitment. PLoS Biology 7:e1000177.
Turpeinen A. M., Wubert J., Aro A., Lorenz R., Mu-tanen M. 1998. Similar effects of diets rich instearic acid or trans-fatty acids on platelet functionand endothelial prostacyclin production in hu-mans. Arteriosclerosis, Thrombosis, and Vascular Biol-ogy 18:316–322.
van der Kooij D., Hijnen W. A. 1988. Nutritionalversatility and growth kinetics of an Aeromonas hy-drophila strain isolated from drinking water. Ap-plied and Environmental Microbiology 54:2842–2851.
Van Deun K., Pasmans F., Van Immerseel F., Ducatelle R.,Haesebrouck F. 2008. Butyrate protects Caco-2 cellsfrom Campylobacter jejuni invasion and translocation.British Journal of Nutrition 100:480–484.
Wang L. L., Johnson E. A. 1992. Inhibition of Listeriamonocytogenes by fatty acids and monoglycerides.Applied and Environmental Microbiology 58:624–629.
Wang L. L., Yang B. K., Parkin K. L., Johnson E. A.1993. Inhibition of Listeria monocytogenes by mono-acylglycerols synthesized from coconut oil andmilkfat by lipase-catalyzed glycerolysis. Journal ofAgricultural and Food Chemistry 41:1000–1005.
Wanten G. J. A., Janssen F. P., Naber A. H. J. 2002.Saturated triglycerides and fatty acids activate neu-trophils depending on carbon chain-length. Euro-pean Journal of Clinical Investigation 32:285–289.
Wille J. J., Kydonieus A. 2003. Palmitoleic acid isomer(C16:1�6) in human skin sebum is effectiveagainst gram-positive bacteria. Skin Pharmacologyand Applied Skin Physiology 16:176–187.
Willett N. P., Morse G. E. 1966. Long-chain fatty acidinhibition of growth of Streptococcus agalactiae in achemically defined medium. Journal of Bacteriology91:2245–2250.
Williams G. C. 1966. Natural selection, the costs ofreproduction, and a refinement of Lack’s princi-ple. American Naturalist 100:687–690.
Wong S. W., Kwon M.-J., Choi A. M. K., Kim H.-P.,Nakahira K., Hwang D. H. 2009. Fatty acids mod-ulate toll-like receptor 4 activation through regu-lation of receptor dimerization and recruitmentinto lipid rafts in a reactive oxygen species-dependent manner. Journal of Biological Chemistry284:27384–27392.
Wu G. D., Chen J., Hoffmann C., Bittinger K., ChenY.-Y., Keilbaugh S. A., Bewtra M., Knights D., Wal-ters W. A., Knight R., Sinha R., Gilroy E., Gupta K.,Baldassano R., Nessel L., Li H., Bushman F. D.,Lewis J. D. 2011. Linking long-term dietary pat-terns with gut microbial enterotypes. Science 334:105–108.
Yeop Han C., Kargi A. Y., Omer M., Chan C. K., WabitschM., O’Brien K. D., Wight T. N., Chait A. 2010. Differ-ential effect of saturated and unsaturated free fattyacids on the generation of monocyte adhesion andchemotactic factors by adipocytes: dissociation of adi-pocyte hypertrophy from inflammation. Diabetes 59:386–396.
Yuk H.-G., Marshall D. L. 2004. Adaptation of Esche-richia coli O157:H7 to pH alters membrane lipidcomposition, verotoxin secretion, and resistanceto simulated gastric fluid acid. Applied and Environ-mental Microbiology 70:3500–3505.
Zapata-Gonzalez F., Rueda F., Petriz J., Domingo P., Villar-roya F., Diaz-Delfin J., de Madariaga M. A., DomingoJ. C. 2008. Human dendritic cell activities are modu-lated by the omega-3 fatty acid, docosahexaenoic acid,
222 Volume 87THE QUARTERLY REVIEW OF BIOLOGY
mainly through PPAR(�):RXR heterodimers: compar-ison with other polyunsaturated fatty acids. Journal ofLeukocyte Biology 84:1172–1182.
Zenhom M., Hyder A., Kraus-Stojanowic I., AuingerA., Roeder T., Schrezenmeir J. 2011. PPAR�-dependent peptidoglycan recognition protein 3(PGlyRP3) expression regulates proinflammatorycytokines by microbial and dietary fatty acids. Im-munobiology 216:715–724.
Zhao G., Etherton T. D., Martin K. R., Vanden HeuvelJ. P., Gillies P. J., West S. G., Kris-Etherton P. M.2005. Anti-inflammatory effects of polyunsatu-rated fatty acids in THP-1 cells. Biochemical andBiophysical Research Communications 336:909–917.
Zhao L., Kwon M.-J., Huang S., Lee J. Y., Fukase K.,Inohara N., Hwang D. H. 2007. Differential mod-ulation of nods signaling pathways by fatty acids inhuman colonic epithelial HCT116 cells. Journal ofBiological Chemistry 282:11618–11628.
Zheng C. J., Yoo J.-S., Lee T.-G., Cho H.-Y., Kim Y.-H.,Kim W.-G. 2005. Fatty acid synthesis is a target forantibacterial activity of unsaturated fatty acids.FEBS Letters 579:5157–5162.
Zuk M., Stoehr A. M. 2002. Immune defense and hostlife history. American Naturalist 160(Supplement4):S9–S22.
Handling Editor: Daniel Dykhuizen
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