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• W2169592605 abstract "Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder referred to gastroenterologists. Although the pathophysiology remains unclear, accumulating evidence points to the presence of low-level immune activation both in the gut and systemically. Circulating polyunsaturated fatty acids (PUFA) have recently attracted attention as being altered in a variety of disease states. Arachidonic acid (AA), in particular, has been implicated in the development of a pro-inflammatory profile in a number of immune-related disorders. AA is the precursor of a number of important immunomodulatory eicosanoids, including prostaglandin E2 (PGE2) and leukotriene B4 (LTB4). We investigated the hypothesis that elevated plasma AA concentrations in plasma contribute to the proposed pro-inflammatory profile in IBS. Plasma AA and related PUFA were quantified by gas chromatography analysis in IBS patients and controls. Both PGE2 and LTB4 were measured in serum using commercially available ELISA assays. AA concentrations were elevated in our patient cohort compared with healthy controls. Moreover, we demonstrated that this disturbance in plasma AA concentrations leads to downstream elevations in eicosanoids. Together, our data identifies a novel proinflammatory mechanism in irritable bowel syndrome and also suggests that elevated arachidonic acid levels in plasma may serve as putative biological markers in this condition. Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder referred to gastroenterologists. Although the pathophysiology remains unclear, accumulating evidence points to the presence of low-level immune activation both in the gut and systemically. Circulating polyunsaturated fatty acids (PUFA) have recently attracted attention as being altered in a variety of disease states. Arachidonic acid (AA), in particular, has been implicated in the development of a pro-inflammatory profile in a number of immune-related disorders. AA is the precursor of a number of important immunomodulatory eicosanoids, including prostaglandin E2 (PGE2) and leukotriene B4 (LTB4). We investigated the hypothesis that elevated plasma AA concentrations in plasma contribute to the proposed pro-inflammatory profile in IBS. Plasma AA and related PUFA were quantified by gas chromatography analysis in IBS patients and controls. Both PGE2 and LTB4 were measured in serum using commercially available ELISA assays. AA concentrations were elevated in our patient cohort compared with healthy controls. Moreover, we demonstrated that this disturbance in plasma AA concentrations leads to downstream elevations in eicosanoids. Together, our data identifies a novel proinflammatory mechanism in irritable bowel syndrome and also suggests that elevated arachidonic acid levels in plasma may serve as putative biological markers in this condition. Irritable bowel syndrome (IBS) is a common and potentially disabling, though nonfatal, medical disorder that can affect up to 20% of the population. It is the most common functional gastrointestinal disorder referred to gastroenterologists (1Ersryd A. Posserud I. Abrahamsson H. Simren M. Subtyping the irritable bowel syndrome by predominant bowel habit: Rome II versus Rome III.Aliment. Pharmacol. Ther. 2007; 26: 953-961Crossref PubMed Scopus (65) Google Scholar). Although it has evolved over the years in terms of nomenclature (2Quigley E.M. Changing face of irritable bowel syndrome.World J. Gastroenterol. 2006; 12: 1-5Crossref PubMed Scopus (55) Google Scholar, 3Spiller R.C. Irritable bowel syndrome.Br. Med. Bull. 2004; 72: 15-29Crossref PubMed Scopus (57) Google Scholar), classification (4Boyce P.M. Koloski N.A. Talley N.J. Irritable bowel syndrome according to varying diagnostic criteria: are the new Rome II criteria unnecessarily restrictive for research and practice?.Am. J. Gastroenterol. 2000; 95: 3176-3183Crossref PubMed Google Scholar, 5Drossman D.A. Camilleri M. Mayer E.A. Whitehead W.E. AGA technical review on irritable bowel syndrome.Gastroenterology. 2002; 123: 2108-2131Abstract Full Text Full Text PDF PubMed Scopus (1211) Google Scholar, 6Fass R. Longstreth G.F. Pimentel M. Fullerton S. Russak S.M. Chiou C.F. Reyes E. Crane P. Eisen G. McCarberg B. et al.Evidence- and consensus-based practice guidelines for the diagnosis of irritable bowel syndrome.Arch. Intern. Med. 2001; 161: 2081-2088Crossref PubMed Scopus (76) Google Scholar), and appreciation of its frequency (7Gilkin Jr, R.J. The spectrum of irritable bowel syndrome: a clinical review.Clin. Ther. 2005; 27: 1696-1709Abstract Full Text PDF PubMed Scopus (38) Google Scholar), a poor understanding of disease pathophysiology has remained a constant. According to the Rome III criteria, a symptom-based classification system, the disease-defining symptom profile encompasses abdominal pain and an altered bowel habit, with distension, bloating, and a variety of disturbances in defecatory function being additional features (8Clarke G. Quigley E.M. Cryan J.F. Dinan T.G. Irritable bowel syndrome: towards biomarker identification.Trends Mol. Med. 2009; 15: 478-489Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar). The disorder is increasingly viewed as a disorder of the brain-gut axis, a construct describing a bidirectional interaction between the gastrointestinal tract (GIT), incorporating the intestinal epithelial barrier, the mucosa-associated lymphoid tissue (MALT), gut muscle and the enteric nervous system (ENS), and the central nervous system (CNS) (9Ringel Y. Drossman D.A. Irritable bowel syndrome: classification and conceptualization.J. Clin. Gastroenterol. 2002; 35 (Suppl. 1): S7-S10Crossref PubMed Scopus (31) Google Scholar, 10Van Oudenhove L. Demyttenaere K. Tack J. Aziz Q. Central nervous system involvement in functional gastrointestinal disorders.Best Pract. Res. Clin. Gastroenterol. 2004; 18: 663-680Crossref PubMed Scopus (152) Google Scholar). Most recently, the proposal that low-grade inflammation, as evidenced by the release of mast cell mediators and activation of lymphocytes in the colo-rectal mucosa and by the detection of elevated levels of pro-inflammatory cytokines in serum (8Clarke G. Quigley E.M. Cryan J.F. Dinan T.G. Irritable bowel syndrome: towards biomarker identification.Trends Mol. Med. 2009; 15: 478-489Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar, 11Dinan T.G. Quigley E.M. Ahmed S.M. Scully P. O'Brien S. O'Mahony L. O'Mahony S. Shanahan F. Keeling P.W. Hypothalamic-pituitary-gut axis dysregulation in irritable bowel syndrome: plasma cytokines as a potential biomarker?.Gastroenterology. 2006; 130: 304-311Abstract Full Text Full Text PDF PubMed Scopus (530) Google Scholar, 12Spiller R. Irritable bowel syndrome–the new inflammatory bowel disease?.Clin. Med. 2008; 8: 417-419Crossref PubMed Scopus (4) Google Scholar, 13Macsharry J. O'Mahony L. Fanning A. Bairead E. Sherlock G. Tiesman J. Fulmer A. Kiely B. Dinan T.G. Shanahan F. et al.Mucosal cytokine imbalance in irritable bowel syndrome.Scand. J. Gastroenterol. 2008; 43: 1467-1476Crossref PubMed Scopus (147) Google Scholar), has provided a new dimension to this paradigm. The source of this low-grade inflammation, or immune activation, whether luminal or central, has remained elusive. Polyunsaturated fatty acids (PUFA) and their metabolites have been shown to influence inflammatory processes (14Calder P.C. Polyunsaturated fatty acids and inflammation.Biochem. Soc. Trans. 2005; 33: 423-427Crossref PubMed Scopus (259) Google Scholar). Moreover, a pro-inflammatory PUFA profile has recently been reported in the maternal separation rodent model, an animal model of IBS (15Clarke G. O'Mahony S.M. Hennessy A.A. Ross P. Stanton C. Cryan J.F. Dinan T.G. Chain reactions: early-life stress alters the metabolic profile of plasma polyunsaturated fatty acids in adulthood.Behavioural Brain Res. 2009; 205: 319-321Crossref PubMed Scopus (30) Google Scholar). However, it has not been extensively studied in this regard in the clinical setting even though it may provide some new insights into disease pathophysiology. The fatty acid composition of the body is largely determined by dietary intake (16Flower R.J. Perretti M. Controlling inflammation: a fat chance?.J. Exp. Med. 2005; 201: 671-674Crossref PubMed Scopus (38) Google Scholar). Western society has a high ratio of ω-6 PUFA compared with ω-3 PUFA largely due to a high consumption of ω-6–rich vegetable oils in comparison to a low consumption of ω-3–rich foods such as oily fish (17Mills S.C. Windsor A.C. Knight S.C. The potential interactions between polyunsaturated fatty acids and colonic inflammatory processes.Clin. Exp. Immunol. 2005; 142: 216-228Crossref PubMed Scopus (74) Google Scholar). The dietary dominance of the ω-6 fatty acids favors the elaboration of pro-inflammatory mediators produced along ω-6 metabolic pathways over less inflammatory ω-3 pathway metabolites. This imbalance, with a shift in a pro-inflammatory direction, has been implicated in a number of diseases, including cardiovascular disease (18Das U.N. Beneficial effect(s) of n-3 fatty acids in cardiovascular diseases: but, why and how?.Prostaglandins Leukot. Essent. Fatty Acids. 2000; 63: 351-362Abstract Full Text PDF PubMed Scopus (239) Google Scholar), depression (19Dinan T. Siggins L. Scully P. O'Brien S. Ross P. Stanton C. Investigating the inflammatory phenotype of major depression: focus on cytokines and polyunsaturated fatty acids.J. Psychiatr. Res. 2009; 43: 471-476Crossref PubMed Scopus (57) Google Scholar, 20Su K.P. Huang S.Y. Chiu T.H. Huang K.C. Huang C.L. Chang H.C. Pariante C.M. Omega-3 fatty acids for major depressive disorder during pregnancy: results from a randomized, double-blind, placebo-controlled trial.J. Clin. Psychiatry. 2008; 69: 644-651Crossref PubMed Scopus (249) Google Scholar) and a variety of inflammatory states (21Simopoulos A.P. Omega-3 fatty acids in health and disease and in growth and development.Am. J. Clin. Nutr. 1991; 54: 438-463Crossref PubMed Scopus (1847) Google Scholar). Moreover, the biological significance of this ratio in these disease states is confirmed by studies showing that dietary manipulations aimed at reducing ω-6 dominance can result in favorable disease outcomes with, for example, a reduction of the ω-6:ω-3 ratio to less than 4:1 being credited with reduced mortality in cardiovascular disease (17Mills S.C. Windsor A.C. Knight S.C. The potential interactions between polyunsaturated fatty acids and colonic inflammatory processes.Clin. Exp. Immunol. 2005; 142: 216-228Crossref PubMed Scopus (74) Google Scholar). This focus on the pro-inflammatory potential of the ω-6 fatty acids has, in particular, been directed toward the role of arachidonic acid (AA) and its metabolites as inflammatory mediators (22Calder P.C. Polyunsaturated fatty acids, inflammatory processes and inflammatory bowel diseases.Mol. Nutr. Food Res. 2008; 52: 885-897Crossref PubMed Scopus (361) Google Scholar). AA is a 20-carbon PUFA that is derived from ω-6 fatty acids and subsequently enters a biochemical cascade to give rise to potent immunomodulatory eicosanoids including prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) (23Eberhart C.E. Dubois R.N. Eicosanoids and the gastrointestinal tract.Gastroenterology. 1995; 109: 285-301Abstract Full Text PDF PubMed Scopus (407) Google Scholar). Given the dietary factors outlined above, AA is the major substrate for synthesis of these eicosanoids, produced by the action of cylcooxygenase and lipoxygenase enzymes, respectively, in Western societies (22Calder P.C. Polyunsaturated fatty acids, inflammatory processes and inflammatory bowel diseases.Mol. Nutr. Food Res. 2008; 52: 885-897Crossref PubMed Scopus (361) Google Scholar). These prostaglandins and leukotrienes can be biologically active even at very low concentrations, and thus, minor alterations in AA status can induce profound downstream consequences (23Eberhart C.E. Dubois R.N. Eicosanoids and the gastrointestinal tract.Gastroenterology. 1995; 109: 285-301Abstract Full Text PDF PubMed Scopus (407) Google Scholar). Interestingly, PGE2 has been shown to induce IL-6 synthesis in macrophages (24Bagga D. Wang L. Farias-Eisner R. Glaspy J.A. Reddy S.T. Differential effects of prostaglandin derived from omega-6 and omega-3 polyunsaturated fatty acids on COX-2 expression and IL-6 secretion.Proc. Natl. Acad. Sci. USA. 2003; 100: 1751-1756Crossref PubMed Scopus (537) Google Scholar). Elevated IL-6 levels have, to date, represented one of the most robust findings supportive of immune activation in IBS (11Dinan T.G. Quigley E.M. Ahmed S.M. Scully P. O'Brien S. O'Mahony L. O'Mahony S. Shanahan F. Keeling P.W. Hypothalamic-pituitary-gut axis dysregulation in irritable bowel syndrome: plasma cytokines as a potential biomarker?.Gastroenterology. 2006; 130: 304-311Abstract Full Text Full Text PDF PubMed Scopus (530) Google Scholar, 25Dinan T.G. Clarke G. Quigley E.M. Scott L.V. Shanahan F. Cryan J. Cooney J. Keeling P.W. Enhanced cholinergic-mediated increase in the pro-inflammatory cytokine IL-6 in irritable bowel syndrome: role of muscarinic receptors.Am. J. Gastroenterol. 2008; 103: 2570-2576Crossref PubMed Scopus (123) Google Scholar, 26Liebregts T. Adam B. Bredack C. Roth A. Heinzel S. Lester S. Downie-Doyle S. Smith E. Drew P. Talley N.J. et al.Immune activation in patients with irritable bowel syndrome.Gastroenterology. 2007; 132: 913-920Abstract Full Text Full Text PDF PubMed Scopus (520) Google Scholar). Despite the importance of the AA cascade, the limited data available on PUFA in IBS have not focused on either the parent molecule or the immunomodulatory metabolites produced along the pathway (27Kilkens T.O. Honig A. Maes M. Lousberg R. Brummer R.J. Fatty acid profile and affective dysregulation in irritable bowel syndrome.Lipids. 2004; 39: 425-431Crossref PubMed Scopus (12) Google Scholar). In this study we hypothesized that the inflammatory signature in IBS is derived from an increased dominance of ω-6 PUFA over their ω-3 counterparts, leading to an increased input to the AA cascade. To test this theory, we measured the plasma PUFA profile in IBS patients and healthy controls and also examined possible downstream alterations in eicosanoid production. The analysis endpoints for this study were total plasma ω-6 content, total plasma ω-3 content, the ω-6:ω-3 ratio, plasma AA concentrations, serum PGE2 concentrations, and serum LTB4 concentrations. Female patients were recruited from a university database of IBS patients. The database consisted of people who had either attended gastroenterology clinics at Cork University Hospital or had responded to direct advertisement on the university campus or local newspaper regarding participation in IBS research. Individuals aged between 18 and 65 years who satisfied Rome II criteria for IBS and in whom organic gastrointestinal diseases and clinically significant systemic diseases had been excluded were considered for inclusion in the study. Pregnant women, individuals with known lactose intolerance or immunodeficiency, or individuals who had any recent transient illness (i.e., within 2 weeks of participation in the study), such as viral illnesses or chest infections, were excluded. A total of 67 subjects, 41 patients with IBS and 26 healthy, sex-matched controls of comparable age and BMI, gave fully informed consent to take part in this study, which had local ethics committee approval. Each potentially eligible patient was evaluated by a review of clinical history, performance of a physical examination, and measurement of full blood count and serum biochemistry, with any clinically significant abnormalities leading to exclusion. The age (mean ± SD) of the patients was 45 ± 11.74 years, and the age of the comparison group was 39.04 ± 12.78. All patients and healthy comparison subjects were drug free, including anti-inflammatory medications. The study was powered to detect differences in fatty acid concentrations at the P < 0.05 level between controls and IBS patients but not within patient subgroups. On arrival at the clinical investigation laboratory at 08.30 h, each subject completed the self report patient health questionnaire (PHQ) to assess the presence of major depression. This is a reliable and valid instrument that was developed as a diagnostic tool to be used in primary care (28Spitzer R.L. Kroenke K. Williams J.B. Validation and utility of a self-report version of PRIME-MD: the PHQ primary care study. Primary Care Evaluation of Mental Disorders.Patient Health Questionnaire. JAMA. 1999; 282: 1737-1744Google Scholar). It tests for the presence of major depression using diagnostic criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). The responses on the depression subscale of the questionnaire can also be used as a dimensional tool to rate the severity of depression (29Kroenke K. Spitzer R.L. Williams J.B. The PHQ-9: validity of a brief depression severity measure.J. Gen. Intern. Med. 2001; 16: 606-613Crossref PubMed Scopus (23195) Google Scholar). In addition to the PHQ, clinical severity of IBS was evaluated using self report ordinal scales in accordance with a previously published method (30Bleijenberg G. Fennis J.F. Anamnestic and psychological features in diagnosis and prognosis of functional abdominal complaints: a prospective study.Gut. 1989; 30: 1076-1081Crossref PubMed Scopus (40) Google Scholar, 31van der Horst H.E. van Dulmen A.M. Schellevis F.G. van Eijk J.T. Fennis J.F. Bleijenberg G. Do patients with irritable bowel syndrome in primary care really differ from outpatients with irritable bowel syndrome?.Gut. 1997; 41: 669-674Crossref PubMed Scopus (69) Google Scholar). This involved subjects rating the severity of their IBS symptoms on a four-point ordinal scale (0-–3) with regard to each abdominal complaint, interference with daily activities, and avoidance behavior as a result of complaints. A summarizing severity score for each patient was determined by taking the sum of the individual scores. Whole blood was collected at 09.00 h in tubes that contained ethylenediametetraacetic acid (EDTA). Samples were centrifuged immediately and the plasma frozen at −80°C until ready for analysis. Serum, where applicable, was generated similarly except that the collection tubes did not contain any anticoagulant. HPLC-grade methanol and chloroform were obtained from Alkem/Reagecon (Cork, Ireland). All other reagents were obtained from Sigma (Germany) unless otherwise stated. Lipids from 1 ml of blood plasma were extracted with 25 ml of chloroform:methanol 2:1 (v/v) containing 5 ppm butylated hydroxytoluene as an antioxidant (32Folch J. Lees M. Sloane Stanley G.H. A simple method for the isolation and purification of total lipides from animal tissues.J. Biol. Chem. 1957; 226: 497-509Abstract Full Text PDF PubMed Google Scholar), and the solvent was removed via gentle evaporation at 45°C under nitrogen gas. Phospholipids were then separated by solid phase extraction using 500 mg NH2 phase columns (Phenomenex, UK) as described previously (33Bondia-Pons I. Morera-Pons S. Castellote A.I. Lopez-Sabater M.C. Determination of phospholipid fatty acids in biological samples by solid-phase extraction and fast gas chromatography..J. Chromatography. 2006.; 1116: 204-208Crossref PubMed Scopus (33) Google Scholar). Phospholipids were transesterified as previously described (34Park P. Goins R. In situ preparation of fatty acid methyl esters for analysis of fatty acid composition in foods.J. Food Sci. 1994; 59: 1262-1266Crossref Scopus (406) Google Scholar), extracted with 4 mls of hexane and an aliquot taken for gas chromatography (GC) analysis. Fatty acids were quantified as fatty acid methyl esters (FAME) by GC analysis using a Varian 3400 gas liquid chromatograph (Varian 3400 capillary GC, Varian, Walnut Creek, CA) fitted with a flame ionization detector. The results were expressed as a percentage of FAME (%, g/100 g FAME). Separation of the FAME was performed on a Chrompack CP Sil 88 column (Chrompack, Middlelburg, The Netherlands) 100 m × 0.25mm ID × 20 μm film thickness). Helium was used as a carrier gas at a pressure of 33.7 psi. The injector temperature was 225°C isothermal with a hold time of 5 min and the detector temperature was 250°C. The column temperature was programmed from an initial temperature of 80°C to a final temperature of 200°C, with an initial delay of 8 min (hold time), at a rate of 8.5°C/min during each analysis. The column was held at the final temperature of 200°C for 7 min (final hold time). Collected data were recorded and analyzed on a Minichrom PC system (VG Data Systems, Manchester, UK). Fatty acids were identified based on the retention time of reference standards (Sigma). PGE2 and LTB4 were measured in serum from a reduced subject group of the trial subjects outlined above. From 25 of the patient group (47 ± 10.63 years) and 19 of the control group (36.21 ± 11.87 years), serum samples in addition to the plasma samples were prepared. Separate Assay Designs EIA assay kits (Cambridge Biosciences, UK) were used to measure the analytes, and the assays were performed as per the manufacturer's instructions. Data were expressed as mean values ± SEM. Data were analyzed by Student-test, one way ANOVA, ANCOVA, and by Dunnets multiple comparison posthoc tests as appropriate. Correlations were assessed according to the Pearson product moment correlation. DSM-IV major depression was comorbid in 41% (17 out of 41) of IBS patients. None of the control group (n = 26) met criteria for current depression. Twenty-two per cent (9 out of 41) of patients rated their IBS symptoms as mild (a sum score of 3 or less on the severity scale); 41% (17 out of 41) reported symptoms of moderate severity; and 37% (15 out of 41) reported symptoms which were severe in nature (i.e., a score of 6 or greater on the severity scale). Twelve of the IBS cohort were classified as having diarrhea-predominant IBS (D-IBS), 9 as constipation-predominant (C-IBS), and 20 had an alternating bowel habit (A-IBS). In addition, 17 of the IBS group had currently active symptoms (CA), 17 were categorized as recently active (RA), and 7 were in a quiescent disease phase (Q). There was no difference between plasma total ω-6 content in IBS compared with controls (32.76 ± 0.48 versus 32.59 ± 0.61 g/100 g fatty acid methyl esters (FAME); t = 0.22, df = 65, P = 0.83). An ANOVA did not reveal any differences between disease subtype or disease status (Table 1).TABLE 1PUFA concentrations (g/100 g FAME), ω-6:ω-3 ratio, and eicosanoid concentrations (pg/ml) in IBS according to disease subtype and status.Disease SubtypeDisease StatusParameterD-IBSC-IBSA-IBSF, (df), PCARAQF, (df), PTotal ω-633.16 ± 0.8632.39 ± 0.9432.69 ± 0.760.13, (3,63), 0.9532.47 ± 0.4932.05 ± 0.8735.19 ± 1.191.88, (3,63), 0.14Total ω-34.49 ± 0.305.36 ± 0.785.02 ± 0.561.98, (3,63), 0.135.04 ± 0.435.20 ± 0.664.07 ± 0.382.22, (3,63), 0.09ω-6:ω-37.89 ± 0.717.06 ± 1.568.27 ± 1.071.10, (3,63), 0.367.51 ± 0.888.81 ± 1.239.34 ± 0.941.24, (3,63), 0.30AA8.39 ± 0.418.05 ± 0.548.81 ± 0.422.03, (3,63), 0.129.09 ± 0.547.90 ± 0.608.63 ± 0.543.02, (3,63), 0.04aP < 0.05, one way ANOVA.PGE21835 ± 362.81115 ± 202.41500 ± 187.53.42, (3, 40), 0.03aP < 0.05, one way ANOVA.1531 ± 3641431 ± 142.61655 ± 527.62.41 (3, 40), 0.08LTB4339 ± 83.57331.2 ± 66.57331 ± 31.331.53, (3, 33), 0.22361 ± 78.51319.7 ± 38.34324.3 ± 65.991.65 (3, 33), 0.2Abbreviations: AA, arachidonic acid; A-IBS, alternating IBS; C-IBS, constipation-predominant IBS; CA, currently active; D-IBS, diarrhea-predominant IBS; FAME, fatty acid methyl esters; LTB4, leukotriene B4; PGE2, prostaglandin E2; PUFA, polyunsaturated fatty acid; Q, quiescent; RA, recently active.a P < 0.05, one way ANOVA. Open table in a new tab Abbreviations: AA, arachidonic acid; A-IBS, alternating IBS; C-IBS, constipation-predominant IBS; CA, currently active; D-IBS, diarrhea-predominant IBS; FAME, fatty acid methyl esters; LTB4, leukotriene B4; PGE2, prostaglandin E2; PUFA, polyunsaturated fatty acid; Q, quiescent; RA, recently active. Plasma total ω-3 content was significantly elevated in the IBS cohort compared with controls (4.94 ± 0.33 versus 3.88 ± 0.30 g/100 g FAME; t = 2.21, df = 65, P = 0.03). An ANOVA analysis did not reveal any differences between disease subtypes or status (Table 1). There was a trend toward a decreased ω-6:ω-3 ratio in the IBS patients relative to control subjects (8.03 ± 0.64 versus 10.25 ± 1.17; t = 1.81, df = 65, P = 0.07). An ANOVA analysis did not highlight any differences between disease subtypes or disease status (Table 1). Plasma AA concentrations were significantly elevated in IBS patients compared with controls (8.52 ± 0.26 versus 7.53 ± 0.37 g/100 g FAME; t = 2.22, df = 65, P = 0.029) (Fig. 1A). An ANOVA analysis revealed that the increase observed could not be assigned to a particular disease subtype (Table 1). An ANOVA analysis followed by a Dunnets multiple comparison posthoc test revealed that the currently active subgroup had significantly elevated plasma AA concentrations compared with control levels (9.09 ± 0.54 versus 7.53 ± 0.37 g/100 g FAME; q = 2.86, df = [3, 63], P < 0.05) (Fig. 1B). An ANCOVA analysis revealed no influence of smoking habits on these results (F = 1.60, df = [1, 63], P = 0.21). PGE2 serum concentrations were significantly elevated in the IBS group compared with controls (1490 ± 142.3 versus 934.2 ± 145.7 pg/ml; t = 2.69, df = 42, P = 0.01) (Fig. 2A). An ANOVA analysis followed by Dunnets multiple comparison posthoc test revealed that the D-IBS subtype had significantly elevated PGE2 levels compared with controls (1835 ± 362.8 versus 934.2 ± 145.7 pg/ml; q = 2.663, df = [3, 40], P < 0.05) (Fig. 2B). A similar analysis across disease status subgroups revealed a nonsignificant trend toward increased PGE2 levels in all categories (Table 1). Technical reasons prevented the measurement of LTB4 levels in two of the control samples and four of the patient samples. LTB4 serum concentrations were significantly elevated in the IBS cohort compared with controls (332.2 ± 31.33 versus 226.0 ± 36.70 pg/ml; t = 2.21, df = 35, P = 0.03) (Fig. 3). An ANOVA analysis did not reveal any differences between IBS subtypes or status (Table 1). An ANCOVA analysis revealed no influence of smoking habits (PGE2: F = 0.85, df = [1, 40], P = 0.36; LTB4: F = 0.66, df = [1, 33], P = 0.42) or age (PGE2: F = 0.01, df = [1, 40], P = 0.9; LTB4: F = 0.66, df = [1, 33], P = 0.42) on these results.Fig. 3Serum LTB4 levels (pg/ml) in healthy female controls (n = 19) and female IBS patients (n = 25) (P < 0.05, t-test). IBS, irritable bowel syndrome; LTB4, leukotriene B4.View Large Image Figure ViewerDownload Hi-res image Download (PPT) There was no correlation between IBS symptom severity and plasma AA levels (Pearson product moment correlation, r = 0.16, df = 39, P = 0.33). Neither was there a correlation between depression scores and plasma AA levels (Pearson product moment correlation, r = 0.17, df = 39, P = 0.30). Plasma AA levels were nonsignificantly elevated regardless of whether they are classified according to IBS severity (8.49 ± 0.61 g/100 g FAME in the mild group, 8.49 ± 0.43 in the moderate group, and 8.57 ± 0.63 in the severe group; F = 1.60, df = [3, 63], P = 0.20) (Fig. 4A) or ± depressive comorbidity (8.78 ± 0.42 in the depressed subgroup and 8.33 ± 0.34 in the nondepressed subgroup; F = 2.78, df = [2, 64], P = 0.07) (Fig. 4B). Additional statistical analysis revealed no correlation between depression scores and either serum PGE2 or LTB4 concentrations. Nor was there a correlation between IBS symptom severity and serum PGE2 or LTB4 concentrations (unpublished observations). Here we show, what is to our knowledge, the first demonstration of altered circulating PUFA metabolites in IBS. The principal finding in this study is that plasma AA concentrations were significantly elevated in the IBS cohort compared with controls. Although the study was not powered to detect IBS subgroup differences, an analysis of the data according to disease status revealed that the data was robust enough to indicate that it was the currently active IBS cohort that made the largest contribution to the elevated plasma AA concentrations. Although a further analysis according to disease subtype (C-IBS, A-IBS, or D-IBS) did not yield any statistically significant results, there appeared to be a uniform increase across all disease subtypes. Interestingly, a previous study that examined plasma fatty acid profiles in a mixed gender IBS cohort did not report any alterations (27Kilkens T.O. Honig A. Maes M. Lousberg R. Brummer R.J. Fatty acid profile and affective dysregulation in irritable bowel syndrome.Lipids. 2004; 39: 425-431Crossref PubMed Scopus (12) Google Scholar). However, although that study did report AA concentrations, it was not one of its statistical endpoint measures nor did it examine the inflammatory mediators produced along the AA cascade. Moreover, it did not take account of possible gender differences in PUFA profiles that have been previously reported (35Childs C.E. Romeu-Nadal M. Burdge G.C. Calder P.C. Gender differences in the n-3 fatty acid content of tissues.Proc. Nutr. Soc. 2008; 67: 19-27Crossref PubMed Scopus (171) Google Scholar). Correlation analyses revealed that there was no relationship between plasma AA concentrations and IBS symptom severity, suggesting that elevated AA is not a direct cause of IBS. Additionally, if the data is grouped according to those with mild, moderate, or severe IBS, the increase is evident i" @default.
• W2169592605 created "2016-06-24" @default.
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• W2169592605 date "2010-05-01" @default.
• W2169592605 modified "2023-10-16" @default.
• W2169592605 title "Marked elevations in pro-inflammatory polyunsaturated fatty acid metabolites in females with irritable bowel syndrome" @default.
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