The objective of the current study was to characterize the profile of oral metabolites in HIV-infected patients using metabolomics. Oral wash samples were collected from 12 HIV-infected and 12 healthy individuals (matched for age, sex, and ethnicity), processed, and analyzed by metabolomics. We detected 198 identifiable and 85 nonidentifiable metabolites; 27 identifiable metabolites were differentially present (12 increased, 15 decreased) in HIV-infected patients. Elevated metabolites included p-cresol sulfate, nucleotides (e.g., allantoin), and amino acids (e.g., phenylalanine, tryptophan), whereas decreased oral metabolites included fucose, fumarate, and N-acetylglucosamine. Pathway network analysis revealed the largest multinode network in healthy versus HIV-infected patients to involve carbohydrate biosynthesis and degradation. HIV-infected patients on antiretroviral therapy (ART) showed the largest number (12) of statistically significant metabolite correlation differences compared with healthy controls. Interestingly, the oral phenlyalanine:tyrosine ratio increased in ART-naive HIV-infected patients (mean ± SEM = 2.58 ± 0.87) compared with healthy individuals (1.33 ± 0.10, p = 0.062) or ART-experienced patients (1.78 ± 0.30, p = 0.441). This is the first study to reveal differential levels of oral metabolites in HIV-infected patients compared withj healthy volunteers, and that oral phenlyalanine:tyrosine ratio may be a useful marker for noninvasive monitoring of the immune status during HIV infection.
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References
1.
AbeS., HuW., IshibashiH., HasumiK., YamaguchiH.2004. Augmented inhibition of Candida albicans growth by murine neutrophils in the presence of a tryptophan metabolite, picolinic acid. J Infect Chemother, 10:181–184.
2.
BarashI., Manulis-SassonS.2009. Recent evolution of bacterial pathogens: the gall-forming Pantoea agglomerans case. Annu Rev Phytopathol, 47:133–152.
3.
BarnesV.M., TelesR., TrivediH.M., DevizioW., XuT., MitchellM.W.et al.2009. Acceleration of purine degradation by periodontal diseases. J Dent Res, 88:851–855.
4.
BlasiE., MazzollaR., PitzurraL., BarluzziR., BistoniF.1993. Protective effect of picolinic acid on mice intracerebrally infected with lethal doses of Candida albicans. Antimicrob Agents Chemother, 37:2422–2426.
5.
BodeR., BirnbaumD.1991. Regulation of chorismate mutase activity of various yeast species by aromatic amino acids. Antonie Van Leeuwenhoek, 59:9–13.
6.
BodeR., MeloC., BirnbaumD.1984. Absolute dependence of phenylalanine and tyrosine biosynthetic enzyme on tryptophan in Candida maltosa. Hoppe Seylers Z Physiol Chem, 365:799–803.
7.
BozzaS., FallarinoF., PitzurraL., ZelanteT., MontagnoliC., BellocchioS.et al.2005. A crucial role for tryptophan catabolism at the host/Candida albicans interface. J Immunol, 174:2910–2918.
8.
BurchellB., CoughtrieM.W.1997. Genetic and environmental factors associated with variation of human xenobiotic glucuronidation and sulfation. Environ Health Perspect, 105,Suppl 4:739–747.
9.
CantorG.H.2010. Metabolomics and mechanisms: sometimes the fisher catches a big fish. Toxicol Sci, 118:321–323.
10.
ClineM.S., SmootM., CeramiE., KuchinskyA., LandysN., WorkmanC.et al.2007. Integration of biological networks and gene expression data using Cytoscape. Nat Protoc, 2:2366–2382.
11.
CooperT.G.1984. Allantoin degradation by Saccharomyces cerevisiae—a model system for gene regulation and metabolic integration. Adv Enzymol Relat Areas Mol Biol, 56:91–139.
12.
CostaC.R., CohenA.J., FernandesO.F., MirandaK.C., PassosX.S., SouzaL.K.et al.2006. Asymptomatic oral carriage of Candida species in HIV-infected patients in the highly active antiretroviral therapy era. Rev Instit Med Trop Sao Paulo, 48:257–261.
13.
CurtiusH.C., MettlerM., EttlingerL.1976. Study of the intestinal tyrosine metabolism using stable isotopes and gas chromatography-mass spectrometry. J Chromatogr, 126:569–580.
14.
DehavenC.D., EvansA.M., DaiH., LawtonK.A.2010. Organization of GC/MS and LC/MS metabolomics data into chemical libraries. J Cheminform, 2:9.
15.
De LucaA., MontagnoliC., ZelanteT., BonifaziP., BozzaS., MorettiS.et al.2007. Functional yet balanced reactivity to Candida albicans requires TRIF, MyD88, and IDO-dependent inhibition of Rorc. J Immunol, 179:5999–6008.
16.
DenkertC., BudcziesJ., KindT., WeichertW., TablackP., SehouliJ.et al.2006. Mass spectrometry-based metabolic profiling reveals different metabolite patterns in invasive ovarian carcinomas and ovarian borderline tumors. Cancer Res, 66:10795–10804.
17.
DenkertC., BudcziesJ., WeichertW., WohlgemuthG., ScholzM., KindT.et al.2008. Metabolite profiling of human colon carcinoma—deregulation of TCA cycle and amino acid turnover. Mol Cancer, 7:72.
18.
DiamondR.D., ClarkR.A., HaudenschildC.C.1980. Damage to Candida albicans hyphae and pseudohyphae by the myeloperoxidase system and oxidative products of neutrophil metabolism in vitro. J Clin Invest, 66:908–917.
19.
DiehlS.R.2006. Pulling teeth into the genomics era. J Am Dent Assoc, 137,710:712–714.
20.
EvansA.M., DehavenC.D., BarrettT., MitchellM., MilgramE.2009. Integrated, nontargeted ultrahigh performance liquid chromatography/electrospray ionization tandem mass spectrometry platform for the identification and relative quantification of the small-molecule complement of biological systems. Anal Chem, 81:6656–6667.
21.
GaoJ., TarceaV.G., KarnovskyA., MirelB.R., WeymouthT.E., BeecherC.W.et al.2010. Metscape: a Cytoscape plug-in for visualizing and interpreting metabolomic data in the context of human metabolic networks. Bioinformatics, 26:971–973.
22.
GarciaI., TabakL.A.2008. Beyond the “omics”: translating science into improved health. J Am Dent Assoc, 139:392–395.
23.
GiacomelliL., CovaniU.2010. Bioinformatics and data mining studies in oral genomics and proteomics: new trends and challenges. Open Dent J, 4:67–71.
24.
GruenH.E.1959. On the plant growth hormone produced by Rhizopus suinus. Annu Rev Plant Physiol, 10:405–440.
25.
IsikS., KockarF., AydinM., ArslanO., GulerO.O., InnocentiA.et al.2009. Carbonic anhydrase activators: activation of the beta-carbonic anhydrase Nce103 from the yeast Saccharomyces cerevisiae with amines and amino acids. Bioorg Med Chem Lett, 19:1662–1665.
26.
KatzI.J., GerntholtzT.E., Van DeventerM., SchneiderH., NaickerS.2010. Is there a need for early detection programs for chronic kidney disease?Clin Nephrol, 74:113–118.
27.
LevineM., Progulske-FoxA., DenslowN.D., FarmerieW.G., SmithD.M., SwearingenW.T.et al.2001. Identification of lysine decarboxylase as a mammalian cell growth inhibitor in Eikenella corrodens: possible role in periodontal disease. Microb Pathog, 30:179–192.
28.
MarzlufG.A.1997. Genetic regulation of nitrogen metabolism in the fungi. Microbiol Mol Biol Rev, 61:17–32.
29.
MorgenthalK., WeckwerthW., SteuerR.2006. Metabolomic networks in plants: transitions from pattern recognition to biological interpretation. Biosystems, 83:108–117.
30.
MucciA., VaresioL., NegliaR., ColombariB., PastorinoS., BlasiE.2003. Antifungal activity of macrophages engineered to produce IFNgamma: inducibility by picolinic acid. Med Microbiol Immunol, 192:71–78.
31.
NaickerS., FabianJ.2010. Risk factors for the development of chronic kidney disease with HIV/AIDS. Clin Nephrol, 74:51–56.
32.
NarayananT.K., RaoG.R.1976. Beta-indoleethanol and beta-indolelactic acid production by Candida species: their antibacterial and autoantibiotic action. Antimicrob Agents Chemother, 9:375–380.
33.
OhtaT., MasutomiN., TsutsuiN., SakairiT., MitchellM., MilburnM.V.et al.2009. Untargeted metabolomic profiling as an evaluative tool of fenofibrate-induced toxicology in Fischer 344 male rats. Toxicol Pathol, 37:521–535.
34.
PattenC.L., GlickB.R.1996. Bacterial biosynthesis of indole-3-acetic acid. Can J Microbiol, 42:207–220.
35.
PattonL.L., PhelanJ.A., Ramos-GomezF.J., NittayanantaW., ShiboskiC.H., MbuguyeT.L.2002. Prevalence and classification of HIV-associated oral lesions. Oral Dis, 8,Suppl 2:98–109.
36.
PendyalaG., WantE.J., WebbW., SiuzdakG., FoxH.S.2007. Biomarkers for neuroAIDS: the widening scope of metabolomics. J Neuroimmune Pharmacol, 2:72–80.
37.
RaoR.P., HunterA., KashpurO., NormanlyJ.2010. Aberrant synthesis of indole-3-acetic acid in Saccharomyces cerevisiae triggers morphogenic transition, a virulence trait of pathogenic fungi. Genetics, 185:211–220.
38.
RosenbergM.2002. The science of bad breath. Sci Am, 286:72–79.
39.
SchepersE., MeertN., GlorieuxG., GoemanJ., Van der EyckenJ., VanholderR.2007. P-cresylsulphate, the main in vivo metabolite of p-cresol, activates leucocyte free radical production. Nephrol Dial Transplant, 22:592–596.
SedgleyC.M., SamaranayakeL.P.1994. The oral prevalence of aerobic and facultatively anaerobic Gram-negative rods and yeasts in Hong Kong Chinese. Arch Oral Biol, 39:459–466.
42.
ShahP., NanduriB., SwiatloE., MaY., PendarvisK.2010. Polyamine biosynthesis and transport mechanisms are crucial for fitness and pathogenesis of Streptococcus pneumoniae. MicrobiologyOct 21 [Epub Ahead of Print].
43.
ShannonP., MarkielA., OzierO., BaligaN.S., WangJ.T., RamageD.et al.2003. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res, 13:2498–2504.
44.
ShiboskiC.H., PattonL.L., Webster-CyriaqueJ.Y., GreenspanD., TraboulsiR.S., GhannoumM.et al.2009. The Oral HIV/AIDS Research Alliance: updated case definitions of oral disease endpoints. J Oral Pathol Med, 38:481–488.
45.
SreekumarA., PoissonL.M., RajendiranT.M., KhanA.P., CaoQ., YuJ.et al.2009. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature, 457:910–914.
46.
SugimotoM., WongD.T., HirayamaA., SogaT., TomitaM.2010. Capillary electrophoresis mass spectrometry-based saliva metabolomics identified oral, breast and pancreatic cancer-specific profiles. Metabolomics, 6:78–95.
47.
SuzziG., GardiniF.2003. Biogenic amines in dry fermented sausages: a review. Int J Food Microbiol, 88:41–54.
48.
TakeiM., AndoY., SaitohW., TanimotoT., KiyosawaN., ManabeS.et al.2010. Ethylene glycol monomethyl ether-induced toxicity is mediated through the inhibition of flavoprotein dehydrogenase enzyme family. Toxicol Sci, 118:643–652.
49.
ThimannK.V.1935. On the plant growth hormone produced by Rhizopus suinus. J Biol Chem, 109:279–291.
50.
Varela-EchavarriaA., Montes de Oca-LunaR., Barrera-SaldanaH.A.1988. Uricase protein sequences: conserved during vertebrate evolution but absent in humans. FASEB J, 2:3092–3096.
51.
VogelsG.D., Van der DriftC.1976. Degradation of purines and pyrimidines by microorganisms. Bacteriol Rev, 40:403–468.
52.
VolberdingP.A., DeeksS.G.2010. Antiretroviral therapy and management of HIV infection. Lancet, 376:49–62.
53.
WagnerD.K., Collins-LechC., SohnleP.G.1986. Inhibition of neutrophil killing of Candida albicans pseudohyphae by substances which quench hypochlorous acid and chloramines. Infect Immun, 51:731–735.
54.
WaltersJ.D.1987. Polyamine analysis of human gingival crevicular fluid. J Periodontal Res, 22:522–523.
55.
WhiteP.L., WilliamsD.W., KuriyamaT., SamadS.A., LewisM.A.O., BarnesR.A.2004. Detection of Candida in concentrated oral rinse cultures by real-time PCR. J Clin Microbiol, 42:2101–2107.
56.
YanS.K., WeiB.J., LinZ.Y., YangY., ZhouZ.T., ZhangW.D.2008. A metabonomic approach to the diagnosis of oral squamous cell carcinoma, oral lichen planus and oral leukoplakia. Oral Oncol, 44:477–483.
57.
ZangerleR., KurzK., NeurauterG., KitchenM., SarclettiM., FuchsD.2010. Increased blood phenylalanine to tyrosine ratio in HIV-1 infection and correction following effective antiretroviral therapy. Brain Behav Immun, 24:403–408.
58.
ZhouJ., XuB., HuangJ., JiaX., XueJ., ShiX.et al.2009. 1H NMR-based metabonomic and pattern recognition analysis for detection of oral squamous cell carcinoma. Clin Chim Acta, 401:8–13.
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