Advertisement

Diet, commensals and the intestine as sources of pathogen-associated molecular patterns in atherosclerosis, type 2 diabetes and non-alcoholic fatty liver disease

      Abstract

      Stimulation of the innate immune receptors Toll-like receptor (TLR)-2 and TLR4 has been shown to promote the development of a variety of diseases involving dysregulated metabolism, including atherosclerosis, type 2 diabetes and non-alcoholic fatty liver disease. However, the origin and nature of the agents responsible for stimulating TLR2 or TLR4 signalling in these conditions remain to be clearly identified. This review summarises the evidence supporting the proposal that ‘pathogen-associated molecular patterns’ (PAMPs) derived from dietary and commensal sources may contribute to the chronic inflammatory processes that underpin the development of these diseases via stimulation of TLR2 and TLR4. In particular, insights gained from recent studies employing TLR-transfectant based bioassays to quantify the abundance of PAMPs in foodstuffs and specific commensal compartments are discussed. Finally, the major mechanisms by which TLR-stimulants may gain access to the circulation to promote systemic low-grade inflammation are considered.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Tomkin G.H.
        Atherosclerosis, diabetes and lipoproteins.
        Expert Rev Cardiovasc Ther. 2010; 8: 1015-1029
        • Ferrante Jr., A.W.
        Obesity-induced inflammation: a metabolic dialogue in the language of inflammation.
        J Intern Med. 2007; 262: 408-414
        • Bensinger S.J.
        • Tontonoz P.
        Integration of metabolism and inflammation by lipid-activated nuclear receptors.
        Nature. 2008; 454: 470-477
        • Bjorkbacka H.
        • Kunjathoor V.V.
        • Moore K.J.
        • et al.
        Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signalling pathways.
        Nat Med. 2004; 10: 416-421
        • Shi H.
        • Kokoeva M.V.
        • Inouye K.
        • et al.
        TLR4 links innate immunity and fatty acid-induced insulin resistance.
        J Clin Invest. 2006; 116: 3015-3025
        • Arkan M.C.
        • Hevener A.L.
        • Greten F.R.
        • et al.
        IKK-beta links inflammation to obesity-induced insulin resistance.
        Nat Med. 2005; 11: 191-198
        • Targher G.
        • Arcaro G.
        Non-alcoholic fatty liver disease and increased risk of cardiovascular disease.
        Atherosclerosis. 2007; 191: 235-240
        • Kawai T.
        • Akira S.
        The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors.
        Nat Immunol. 2010; 11: 373-384
        • Tsan M.F.
        • Gao B.
        Endogenous ligands of Toll-like receptors.
        J Leukoc Biol. 2004; 76: 514-519
        • Erridge C.
        Endogenous ligands of TLR2 and TLR4: agonists or assistants?.
        J Leukoc Biol. 2010; 87: 989-999
        • den Dekker W.K.
        • Cheng C.
        • Pasterkamp G.
        • Duckers H.J.
        Toll like receptor 4 in atherosclerosis and plaque destabilization.
        Atherosclerosis. 2010; 209: 314-320
        • Rocha V.Z.
        • Libby P.
        Obesity, inflammation, and atherosclerosis.
        Nat Rev Cardiol. 2009; 6: 399-409
        • Mullick A.E.
        • Tobias P.S.
        • Curtiss L.K.
        Modulation of atherosclerosis in mice by Toll-like receptor 2.
        J Clin Invest. 2005; 115: 3149-3156
        • Madan M.
        • Amar S.
        Toll-like receptor-2 mediates diet and/or pathogen associated atherosclerosis: proteomic findings.
        PLoS ONE. 2008; 3: e3204
        • Michelson K.S.
        • Wong M.H.
        • Shah P.K.
        • et al.
        Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E.
        Proc Natl Acad Sci USA. 2004; 101: 10679-10684
        • Cuaz-Pérolin C.
        • Billiet L.
        • Baugé E.
        • et al.
        Antiinflammatory and antiatherogenic effects of the NF-kappaB inhibitor acetyl-11-keto-beta-boswellic acid in LPS-challenged ApoE-/- mice.
        Arterioscler Thromb Vasc Biol. 2008; 28: 272-277
        • Westerterp M.
        • Berbée J.F.
        • Pires N.M.
        • et al.
        Apolipoprotein C-I is crucially involved in lipopolysaccharide-induced atherosclerosis development in apolipoprotein E-knockout mice.
        Circulation. 2007; 116: 2173-2181
        • Laman J.D.
        • Schoneveld A.H.
        • Moll F.L.
        • van Meurs M.
        • Pasterkamp G.
        Significance of peptidoglycan, a proinflammatory bacterial antigen in atherosclerotic arteries and its association with vulnerable plaques.
        Am J Cardiol. 2002; 90: 119-123
        • Ott S.J.
        • El Mokhtari N.E.
        • Musfeldt M.
        • et al.
        Detection of diverse bacterial signatures in atherosclerotic lesions of patients with coronary heart disease.
        Circulation. 2006; 113: 929-937
        • Erridge C.
        • Burdess A.
        • Jackson A.J.
        • et al.
        Vascular cell responsiveness to Toll-like receptor ligands in carotid atheroma.
        Eur J Clin Invest. 2008; 38: 713-720
        • Wiedermann C.I.
        • Kiechl S.
        • Dunzendorfer S.
        • et al.
        Association of endotoxaemia with carotid atherosclerosis and cardiovascular disease: prospective results from the Bruneck Study.
        J Am Coll Cardiol. 1999; 34: 1975-1981
        • Pussinen P.J.
        • Tuomisto K.
        • Jousilahti P.
        • Havulinna A.S.
        • Sundvall J.
        • Salomaa V.
        Endotoxemia, immune response to periodontal pathogens, and systemic inflammation associate with incident cardiovascular disease events.
        Arterioscler Thromb Vasc Biol. 2007; 27: 1433-1439
        • Caricilli A.M.
        • Nascimento P.H.
        • Pauli J.R.
        • et al.
        Inhibition of toll-like receptor 2 expression improves insulin sensitivity and signaling in muscle and white adipose tissue of mice fed a high-fat diet.
        J Endocrinol. 2008; 199: 399-406
        • Himes R.W.
        • Smith C.W.
        Tlr2 is critical for diet-induced metabolic syndrome in a murine model.
        FASEB J. 2010; 24: 731-739
        • Ehses J.A.
        • Meier D.T.
        • Wueest S.
        • et al.
        Toll-like receptor 2-deficient mice are protected from insulin resistance and beta cell dysfunction induced by a high-fat diet.
        Diabetologia. 2010; 53: 1795-1806
        • Poggi M.
        • Bastelica D.
        • Gual P.
        • et al.
        C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet.
        Diabetologia. 2007; 50: 1267-1276
        • Tsukumo D.M.
        • Carvalho-Filho M.A.
        • Carvalheira J.B.
        • et al.
        Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance.
        Diabetes. 2007; 56: 1986-1998
        • Senn J.J.
        Toll-like receptor-2 is essential for the development of palmitate-induced insulin resistance in myotubes.
        J Biol Chem. 2006; 281: 26865-26875
        • Cani P.D.
        • Amar J.
        • Iglesias M.A.
        • et al.
        Metabolic endotoxemia initiates obesity and insulin resistance.
        Diabetes. 2007; 56: 1761-1772
        • Creely S.J.
        • McTernan P.G.
        • Kusminski C.M.
        • et al.
        Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes.
        Am J Physiol Endocrinol Metab. 2007; 292: E740-E747
        • Al-Attas O.S.
        • Al-Daghri N.M.
        • Al-Rubeaan K.A.
        • et al.
        Changes in endotoxin levels in T2DM subjects on anti-diabetic therapies.
        Cardiovasc Diabetol. 2009; 8: 20
        • Harte A.L.
        • da Silva N.F.
        • Creely S.J.
        • et al.
        Elevated endotoxin levels in non-alcoholic fatty liver disease.
        J Inflamm (Lond). 2010; 7: 15
        • Mehta N.N.
        • McGillicuddy F.C.
        • Anderson P.D.
        • et al.
        Experimental endotoxemia induces adipose inflammation and insulin resistance in humans.
        Diabetes. 2010; 59: 172-181
        • Solga S.F.
        • Diehl A.M.
        Non-alcoholic fatty liver disease: lumen–liver interactions and possible role for probiotics.
        J Hepatol. 2003; 38: 681-687
        • Farrell G.C.
        • Larter C.Z.
        Nonalcoholic fatty liver disease: from steatosis to cirrhosis.
        Hepatology. 2006; 43: S99-S112
        • Rivera C.A.
        • Adegboyega P.
        • van Rooijen N.
        • et al.
        Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis.
        J Hepatol. 2007; 47: 571-579
        • Spruss A.
        • Kanuri G.
        • Wagnerberger S.
        • Haub S.
        • Bischoff S.C.
        • Bergheim I.
        Toll-like receptor 4 is involved in the development of fructose-induced hepatic steatosis in mice.
        Hepatology. 2009; 50: 1094-1104
        • Brun P.
        • Castagliuolo I.
        • Di Leo V.
        • et al.
        Increased intestinal permeability in obese mice: new evidences in the pathogenesis of nonalcoholic steatohepatitis.
        Am J Physiol Gastrointest Liver Physiol. 2007; 292: G518-G525
        • Tomofuji T.
        • Ekuni D.
        • Yamanaka R.
        • et al.
        Chronic administration of lipopolysaccharide and proteases induces periodontal inflammation and hepatic steatosis in rats.
        J Periodontol. 2007; 78: 1999-2006
        • Mathurin P.
        • Deng Q.G.
        • Keshavarzian A.
        • et al.
        Exacerbation of alcoholic liver injury by enteral endotoxin in rats.
        Hepatology. 2000; 32: 1008-1017
        • Hyvärinen K.
        • Tuomainen A.M.
        • Laitinen S.
        • et al.
        Chlamydial and periodontal pathogens induce hepatic inflammation and fatty acid imbalance in apolipoprotein E-deficient mice.
        Infect Immun. 2009; 77: 3442-3449
        • Farhadi A.
        • Gundlapalli S.
        • Shaikh M.
        • et al.
        Susceptibility to gut leakiness: a possible mechanism for endotoxaemia in non-alcoholic steatohepatitis.
        Liver Int. 2008; 28: 1026-1033
        • Thuy S.
        • Ladurner R.
        • Volynets V.
        • et al.
        Nonalcoholic fatty liver disease in humans is associated with increased plasma endotoxin and plasminogen activator inhibitor 1 concentrations and with fructose intake.
        J Nutr. 2008; 138: 1452-1455
        • Miele L.
        • Valenza V.
        • La Torre G.
        • et al.
        Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease.
        Hepatology. 2009; 49: 1877-1887
        • Vyberg M.
        • Ravn V.
        • Andersen B.
        Pattern of progression in liver injury following jejunoileal bypass for morbid obesity.
        Liver. 1987; 7: 271-276
        • Suganami T.
        • Mieda T.
        • Itoh M.
        • Shimoda Y.
        • Kamei Y.
        • Ogawa Y.
        Attenuation of obesity-induced adipose tissue inflammation in C3H/HeJ mice carrying a Toll-like receptor 4 mutation.
        Biochem Biophys Res Commun. 2007; 354: 45-49
        • Erridge C.
        • Attina T.
        • Spickett C.M.
        • Webb D.J.
        A high-fat meal induces low-grade endotoxemia: evidence of a novel mechanism of postprandial inflammation.
        Am J Clin Nutr. 2007; 86: 1286-1292
        • Laugerette F.
        • Vors C.
        • Géloën A.
        • Chauvin M.A.
        • Soulage C.
        • Lambert-Porcheron S.
        • Peretti N.
        • Alligier M.
        • Burcelin R.
        • Laville M.
        • Vidal H.
        • Michalski M.C.
        Emulsified lipids increase endotoxemia: possible role in early postprandial low-grade inflammation.
        J Nutr Biochem. 2010; 22: 53-59
        • Ghoshal S.
        • Witta J.
        • Zhong J.
        • de Villiers W.
        • Eckhardt E.
        Chylomicrons promote intestinal absorption of lipopolysaccharides.
        J Lipid Res. 2009; 50: 90-97
        • Yoshino S.
        • Sasatomi E.
        • Mori Y.
        • Sagai M.
        Oral administration of lipopolysaccharide exacerbates collagen-induced arthritis in mice.
        J Immunol. 1999; 163: 3417-3422
        • Lalla E.
        • Lamster I.B.
        • Hofmann M.A.
        • et al.
        Oral infection with a periodontal pathogen accelerates early atherosclerosis in apoliporotein E-null mice.
        Arterioscler Thromb Vasc Biol. 2003; 23: 1405-1411
        • Kuula H.
        • Salo T.
        • Pirilä E.
        • et al.
        Local and systemic responses in matrix metalloproteinase 8-deficient mice during Porphyromonas gingivalis-induced periodontitis.
        Infect Immun. 2009; 77: 850-859
        • Bahekar A.A.
        • Singh S.
        • Saha S.
        • Molnar J.
        • Arora R.
        The prevalence and incidence of coronary heart disease is significantly increased in periodontitis: a meta-analysis.
        Am Heart J. 2007; 154: 830-837
        • de Oliveira C.
        • Watt R.
        • Hamer M.
        Toothbrushing, inflammation, and risk of cardiovascular disease: results from Scottish Health Survey.
        Br Med J. 2010; 340: c2451
        • Erridge C.
        The capacity of foodstuffs to induce innate immune activation of human monocytes in vitro is dependent on food content of stimulants of Toll-like receptors 2 and 4.
        Br J Nutr. 2010; 20: 1-9
        • Lappin D.F.
        • Sherrabeh S.
        • Erridge C.
        Stimulants of Toll-like receptors 2 and 4 are elevated in saliva of periodontitis patients compared to healthy subjects.
        J Clin Periodontol. 2011; 38: 318-325
        • Dzink J.L.
        • Tanner A.C.
        • Haffajee A.D.
        • Socransky S.S.
        Gram negative species associated with active destructive periodontal lesions.
        J Clin Periodontol. 1985; 12: 648-659
        • Mantilla Gómez S.
        • Danser M.M.
        • Sipos P.M.
        • et al.
        Tongue coating and salivary bacterial counts in healthy/gingivitis subjects and periodontitis patients.
        J Clin Periodontol. 2001; 28: 970-978
        • Berg R.D.
        The indigenous gastrointestinal microflora.
        Trends Microbiol. 1996; 4: 430-435
        • Posserud I.
        • Stotzer P.O.
        • Björnsson E.S.
        • Abrahamsson H.
        • Simrén M.
        Small intestinal bacterial overgrowth in patients with irritable bowel syndrome.
        Gut. 2007; 56: 802-808
        • Erridge C.
        • Duncan S.H.
        • Bereswill S.
        • Heimesaat M.M.
        The induction of colitis and ileitis in mice is associated with marked increases in intestinal concentrations of stimulants of TLRs 2, 4, and 5.
        PLoS One. 2010; 5: e9125
        • Alhawi M.
        • Stewart J.
        • Erridge C.
        • Patrick S.
        • Poxton I.R.
        Bacteroides fragilis signals through Toll-like receptor (TLR) 2 and not through TLR4.
        J Med Microbiol. 2009; 58: 1015-1022
        • DeSesso J.M.
        • Jacobson C.F.
        Anatomical and physiological parameters affecting gastrointestinal absorption in humans and rats.
        Food Chem Toxicol. 2001; 39: 209-228
        • Erridge C.
        Accumulation of stimulants of Toll-like receptor (TLR)-2 and TLR4 in meat products stored at 5 degrees C.
        J Food Sci. 2011; 2: H72-H79
        • Youngner J.S.
        Bacterial lipopolysaccharide: oral route for interferon production in mice.
        Infect Immun. 1972; 6: 646-647
        • Tamai H.
        • Horie Y.
        • Kato S.
        • Yokoyama H.
        • Ishii H.
        Long-term ethanol feeding enhances susceptibility of the liver to orally administered lipopolysaccharides in rats.
        Alcohol Clin Exp Res. 2002; 26: 75S-80S
        • Copeland S.
        • Warren H.S.
        • Lowry S.F.
        • Calvano S.E.
        • Remick D.
        Inflammation and the Host Response to Injury Investigators. Acute inflammatory response to endotoxin in mice and humans.
        Clin Diagn Lab Immunol. 2005; 12: 60-67
        • Bergheim I.
        • Weber S.
        • Vos M.
        • et al.
        Antibiotics protect against fructose-induced hepatic lipid accumulation in mice: role of endotoxin.
        J Hepatol. 2008; 48: 983-992
        • Volynets V.
        • Spruss A.
        • Kanuri G.
        • et al.
        Protective effect of bile acids on the onset of fructose-induced hepatic steatosis in mice.
        J Lipid Res. 2010; 51: 3414-3424
        • Abdelmalek M.F.
        • Suzuki A.
        • Guy C.
        • et al.
        Nonalcoholic Steatohepatitis Clinical Research Network. Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease.
        Hepatology. 2010; 51: 1961-1971