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Amylin and Leptin Signaling Converge on Leptin Receptor Neurons of theNucleus of the Solitary Tract and the Lateral Parabrachial Nucleus in theMurine BrainMichael Rajala, Christa Patterson, Martin Myers

The inherent redundancies in the brain circuitry regulating food intake and body weighthave made single hormone target therapies for weight loss relatively ineffective. Exogenousleptin decreases food intake and body weight in rodents through central activation of thesignaling form of the leptin receptor (LepRb); however, leptin treatment of obese humanpatients is ineffective in producing weight loss. Employing a multi-target approach, recentresults have demonstrated that concurrent treatment with amylin, a nutritionally regulatedpancreatic beta-cell hormone, and leptin can synergistically reduce food intake and promoteweight loss in both rodents and humans. To determine whether amylin and leptin convergeon and activate similar sets of neurons, we examined activation of cFos (a maker of neuronalactivity) following peripheral amylin administration in mice expressing yellow fluorescentprotein only in LepRb neurons (LepRb-YFP). Consistent with known amylin targets, cFoswas induced in the area postrema (AP), the established primary entry point for the centralsatiety action of amylin. Although the AP is devoid of LepRb neurons, amylin also promotedcFos in the nucleus of the solitary tract (NTS)(a known target of AP amylin-sensing neurons),lateral parabrachial nucleus (lPBN), central nucleus of the amygdala (CeA) and severalhypothalamic nuclei (VMH, DMH, LHA); many of these areas contain substantial numberof LepRb neurons. Indeed, amylin induced cFos activation in a significant population ofLepRb neurons within the medial NTS and lPBN, suggesting that these hindbrain LepRbneurons represent a point of convergence for amylin and leptin action. In order to determineif amylin activates other neurons that lie in direct contact with LepRb neurons, we utilizeda mouse model (LepRb-WGA) in which wheat germ agglutinin (WGA) identifies the neuronsin synaptic contact with LepRb neurons. Amylin administration promoted cFos activationin WGA-containing neurons of the medial NTS, revealing a second point of convergenceof leptin and amylin action in the hindbrain. Together, these results reveal multiple pointsof convergence between amylin and leptin signaling in the hindbrain, specifically NTS andLPBN LepRb neurons along with other NTS neurons that are innervated by LepRb neuronsand activated by amylin. Current studies are assessing cFos activation in LepRb neuronsfollowing both leptin and amylin administration in LepRb-YFP mice to test the possibilitythat leptin and amylin regulate these neurons synergistically.

Sa1771

Characterization of Receptors and Signaling Pathways Coupled to UmamiTaste in Enteroendocrine CellsVanitha Bala, Sunila Mahavadi, Vijay Lyall, Karnam S. Murthy, John R. Grider

Recent studies demonstrated that a subset of chemosensing receptors and signaling moleculesin the gastrointestinal mucosa are similar to the gustatory signals in the oral cavity. Activationof these receptors by various tastants is involved in the regulation of food intake, motility,and secretion involving interplay between the enteroendocrine cells and visceral sensoryneurons. Functional sweet and bitter taste receptors have been identified in the gut mucosaand their activation via T1R2/T1R3- and T2R-coupled Gα gustducin signaling, respectively,underlie the secretion of glucagon-like peptide-1 (GLP-1) and cholecystokinin. Umami, afifth sense of taste, perceived in the oral cavity by amino acids such as glutamate, is shownto activate several G protein coupled receptors including metabotropic glutamate receptorsas well as Gαgustducin-coupled T1R1/T1R3 heterodimer receptors. Activation of the lattercauses stimulation of βγ-dependent PLC-β2 activity, IP3-dependent Ca2+ release and Ca2+-dependent nonselective cation channel TRPM5 function. AIM: To determine the expressionof T1R1/T1R3 receptors and the related signaling molecules, and their colocalization withvarious gut peptides in enteroendocrine STC-1 cells. METHODS: STC-1 cells were obtainedfrom ATCC and maintained in culture. Expression of T1R1, T1R3, Gα gustuducin, PLC-β2 and TRPM5 was examined by RT-PCR, western blot and immunohistochemistry (IHC).Colocalization of GLP-1, peptide YY (PYY), and neurotensin (NT) with umami taste-specificT1R1 was examined by IHC. Activation of PLC-β2 in response to umami ligand, monosodiumglutamate (MSG, 10 mM) was examined in cells labeled with [3H]myo-inositol. Stimulationof ERK1/2 activity, and GLP-1 and PYY release in response to MSG was measured byimmunokinase assay and ELISA. RESULTS: RT-PCR, western blot and IHC studies showedthe expression of T1R1, T1R3, Gα gustducin, PLC-β2 and TRPM5 in STC-1 cells. Immuno-histochemistry revealed 82% colocalization of T1R1 with GLP-1, 80% with T1R3, 22% withPYY and 56% with NT. Treatment of cells with MSG caused stimulation of PLC-β2 andERK1/2 activity and induced release of GLP-1 and PYY. The PI-PLC inhibitor U73122reduced the effect of MSG on GLP-1 and PYY release. CONCLUSION. STC-1 cells expressGα gustducin-coupled T1R1/T1R3 receptors and in some cases contain GLP-1, PYY or NT.Activation of these receptors with the umami ligand causes stimulation of PLC-β2 and ERK1/2 activity, and GLP-1 and PYY release. Further studies identifying the luminal chemosensingfactors that regulate the secretion of gut peptides from the enteroendocrine cells will facilitatethe development of therapeutic agents that target these cells to regulate gastrointestinal func-tion.

Sa1772

Gnotobiotic Toll-Like Receptor 5 Deficient Mice Lack Spontaneous Colitis andMetabolic SyndromeMatam Vijay-Kumar, Jesse D. Aitken, Yueju Su, Gayathri Srinivasan, Frederic A. Carvalho,Andrew T. Gewirtz

Introduction: Toll Like Receptor 5 (TLR5), an innate immune receptor expressed basolaterallyby epithelial cells in multiple tissues, detects bacterial flagellin and serves to monitor andmaintain the barrier between the lumen and host tissue. TLR5's function is especiallyimportant in the gut, where it works in concert with other pattern recognition receptors toprotect against pathogenic and opportunistic bacteria. Mice lacking TLR5 (TLR5KO) arepredisposed to developing spontaneous low-grade and robust inflammation resulting in

S-324AGA Abstracts

metabolic syndrome and colitis, respectively. Methods: Embryo transplant was performedto generate gnotobioticmice heterozygous-null for TLR5, which were then bred in gnotobiotichousing to attain gnotobiotic TLR5KO mice and WT littermates. Gnotobiotic 10-12 weekold wild type (WT) and TLR5-deficient (TLR5KO) mice were euthanized in sterile conditionsand analyzed for various metabolic and inflammatory parameters including blood glucose,body and organ weights, tissue myeloperoxidase (MPO) and histology. To verify that thegnotobiotic mice lacked TLR agonists, the ability of cecal contents to elicit an innate immuneresponse (i.e. cytokines) in conventional WT mice was ascertained. Cytokines were analyzedboth in serum and ex vivo colon and small intestinal cultures. Serum and liver lipid contentwere also analyzed as was gene expression in the colon and liver. Metabolic function wasassayed via evaluation of serum glucose, insulin and leptin. Results: WT and TLR5KO micewere confirmed to lack detectable TLR agonists in their feces/cecal contents as these failedto elicit an immune response in conventional mice. Careful comparison of gnotobiotic WTand TLR5KO for a variety of parameters associated with both colitis and metabolic syndromefound no phenotypic distinctions between these groups of mice. Conclusion: Gnotobioticmice lack functionally relevant levels of TLR agonists in the gut indicating TLR activationin the gut is driven by commensal bacteria rather than dietary or host-derived agonists.While conventional TLR5KO are prone to both colitis and metabolic syndrome, rederivationof these mice to the gnotobiotic state makes them phenotypically indistinguishable fromWT gnotobiotic mice. These findings confirm that the previously described phenotypes ofTLR5KO mice result from loss of recognition of intestinal bacteria and are in accord withthe notion that TLR5KO mice are prone to developing gut inflammation due to an inabilityto manage the commensal gut microbiota.

Sa1773

Antibiotics Induced Commensal Flora Disruption Favours Escherichia coliAIEC (LF82) Colonization in Wild Type and NOD2 Knock-out MiceMaryline Drouet, Cécile Vignal, Elisabeth Singer, Luc Dubreuil, Pierre Desreumaux,Christel Neut

Ileal lesions of Crohn's disease (CD) patients are colonized by pathogenic adherent-invasiveEscherichia coli (AIEC). NOD2 gene mutations are risk factors for ileal CD and are associatedwith an abnormal AIEC-induced immune response. AIM: since innate immune system andcommensal microbial colonization are critical to maintain intestinal barrier integrity, weevaluated the impact of commensal microbial colonization disruption induced by short termantibiotic treatment on AIEC LF82 colonization and translocation in wild type (WT) andNOD2 knock-out mice (NOD2KO). MATERIALS: Disruption of commensal microbialcolonization was induced by a 3 days antibiotic treatment (gentamicin 3 mg/kg/d andvancomycin 40 mg/kg/d) administered by oral gavage in NOD2KO (n=75) mice and theirC57/Bl6 WT wild type littermates (n=75). At day 3, mice were infected with 109 CFU AIEConce a day for 2 days. Non infected and infected mice without antibiotic treatment wereused as controls (n=6 per group). Animals were sacrificed at day 1 (n=32), day 30 (n=48)and day 60 (n=48) after AIEC administration. Ileum, colon and mesenteric lymph nodeswere sampled for 1) AIEC quantification in ileal and colonic tissues (detection rate 104cfu/g), 2) bacterial translocation in mesenteric lymph nodes (detection rate 102cfu/g), and 3)evaluation of histological abnormalities and intestinal inflammation. RESULTS: Withoutantibiotic treatment, AIEC was not able to colonize WT and NOD2KO mice at day 1, 30and 60 and did not induce bacterial translocation, histologic ileal and colonic abnormalitiesand/or inflammation. Compared to control animals, commensal microbial disruption inducedby antibiotics led to a significant increase of ileal and colonic adherent AIEC in both NOD2KOmice (respectively 6.23log±0.52 cfu/g ileum and 6.65log±0.27 cfu/g colon) and WT animals(respectively 7.61log±0.27 cfu/g ileum and 8.8log ±0.31 cfu/g colon) at day 1. PersistentAIEC colonization was still observed at day 30 in the ileum and not the colon of bothNOD2KO mice (5.5log±0.71 cfu/g ileum) and WT animals (5.25log ±0.28 cfu/g ileum),disappearing at day 60. Mesenteric translocation of AIEC was observed at day 1 in bothNOD2KO mice (2.4log±0.31) and WT animals (3log±0.07) and was maintained until day30 only in NOD2KO mice (3.46log±0.79). No histologic ileal and colonic abnormalitiesand/or inflammation were observed in NOD2KO mice and their WT littermates treatedwith antibiotics and infected with AIEC. CONCLUSION: WT and NOD2KO mice werespontaneously resistant to AIEC infection. Sustained AIEC colonization in ileal tissues of micewas induced by commensal flora disruption promoted by short term antibiotic treatment,independently of NOD2 expression. In contrast, commensal flora disruption by antibioticsinduced a long term AIEC bacterial translocation in a NOD2 dependent manner.

Sa1774

Defective Macrophage Function in Crohn's Disease: Role of AlternativelyActivated Macrophages in InflammationChristos Karaiskos, Barry N. Hudspith, Tim Elliott, Neil B. Rayment, Vanessa Avgousti,Jonathan Brostoff, Jeremy D. Sanderson

The aetiology of Crohn's disease (CD) involves a genetically determined dysregulated immuneresponse to commensal intestinal microflora. In CD, viable E.coli are found within laminapropria macrophages (MΦs) and using In Vitro models we have shown that E.coli intracellularsurvival is prolonged in CD-derivedΜΦs. It is now recognised that different MΦ subpopula-tions exist, M1 cells are inflammatory cells, M2a cells are involved in tissue repair and M2care regulatory cells that limit inflammation. However, the role these different MΦs play inthis abnormal handling of bacteria in CD is unclear. The aim of this study was to examineIn Vitro M1 and M2 MΦ maturation in CD patients compared to healthy individuals andhow these cells respond to challenge with CD-derived E.coli. To do this we monitoredMΦ morphology, surface markers, cytokine production and intracellular bacterial survival.Peripheral blood monocytes were isolated from CD patients and healthy controls and treatedwith cytokines to generate distinct MΦ subpopulations: IFNγ for M1, IL4/IL13 for M2a andIL10 for M2c. MΦmorphology was assessed by H&E staining and surface marker expressionof CD14, CD16 and CD33, chemokine receptor CCR2, scavenger receptor CD163, costimulatory molecule CD40 and mannose receptor CD206 using flow cytometry. IL10 andTNFα production were measured by ELISA and intracellular E.coli survival was measured

using the gentamicin protection assays. We found that in contrast to M1 MΦ's, both CD-derived M2 populations failed to develop the characteristic MΦ dendrite morphology seenin control macrophages. Surface expression of CD40 in M2 CD-derived MΦs was 3.4-foldlower for M2a and 4.4- fold lower for M2c compared to controls after E.coli challenge.CD163 was higher in M1 CD cells but reduced by 50% in M2 cells compared to healthycells. After E.coli challenge, TNFα production by M2 but not M1 MΦs was significantlylower in CD than in controls (M2a 38%, M2c 27% respectively less than controls) butthere were no differences in IL10 production. Prolonged intracellular survival of E.coli wasdemonstrated in CD M2 cells but effective killing occurred in all M1 CD MΦs and all controlMΦs. In CD, M2 (but not M1) MΦs display abnormal morphological maturation, lowerTNFα levels after E.coli challenge, prolonged intracellular bacterial survival and differencesin surface marker expression. The results are consistent with an innate MΦ defect in CDrelating particularly to a failure of the normal role of M2 MΦs to limit and control inflamma-tion.

Sa1775

STAT3-Mediated Production of Antimicrobial Peptides by Intestinal EpithelialCells Helps Controlling C. rodentium Induced InfectionNadine Wittkopf, Ulrike Billmeier, Claudia Günther, Stefan J. Wirtz, Markus F. Neurath,Christoph Becker

Background and Aims: Infection with Citrobacter rodentium, a murine model pathogen forattaching and effacing Escherichia coli, is widely used to mimic infectious colitis. We havepreviously shown that mice lacking the ability for activation of the transcription factorStat3 in intestinal epithelial cells (IECs) show decreased secretion of antimicrobial peptides.Therefore, we investigated the role of intestinal epithelial Stat3 activation during infectiouscolitis. Methods: Mice were generated with an IEC-specific deletion of Stat3 (Stat3IEC-KO).Control and Stat3IEC-KO mice were orally infected with a luciferase expressing strain ofC. rodentium. Bacterial infestation in the gut was monitored by In-Vivo-imaging of lumines-cence in living micE. colitis was assessed using high resolution colonoscopy. Results: Wecould show that infection of wildtype mice with C. rodentium resulted in activation of Stat3in IECs and that the Stat3-activating cytokines IL-6 and IL-22 were highly induced in thecolon upon infection. Furthermore, C. rodentium infected wildtype mice showed stronginduction of the antimicrobial peptides Reg3g, Reg3b, Cryptdin, Lysozyme, Pla2g5 andPla2g2a concurrent with epithelial activation of Stat3. The analysis of Stat3IEC-KO micerevealed an increased susceptibility to C. rodentium infection as indicated by increasedbacterial load in the gut and more severe tissue damage in the colon. Histological examinationof colonic tissue samples from C. rodentium infected Stat3IEC-KO mice demonstratedincreased infiltration of immune cells, enhanced mucosal hyperplasia and increased epithelialapoptosis. Importantly, Stat3IEC-KO mice showed unexpected invasion of C. rodentium intoother organs such as lung, liver and kidney. Conclusion: Activation of Stat3 in intestinalepithelial cells of wildtype mice during C. rodentium infection suggests an important rolefor Stat3 activation in the course of an infectious colitis. In fact, our data demonstrate thatStat3 deficient mice show an increased susceptibility to experimental infectious colitis anda defective barrier function of the epithelium. Together, these data implicate a protectiverole for Stat3 activation in IECs during C. rodentium infection by controlling bacterial growthby production of antimicrobials and suppression of apoptosis for maintaining the epithelialbarrier integrity.

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The Immunomodulatory Drug FTY720 Prevents Clearance of Citrobacterrodentium Infection in MiceCarola Murphy, Lindsay J. Hall, Grainne Hurley, Aoife Quinlan, Fergus Shanahan,Kenneth Nally, Silvia Melgar

Background: The novel immunomodulatory drug, FTY720, blocks the binding of sphingos-ine-1-phosphate (S1P) to four of its five G-protein coupled receptors (GPCRs), namely S1P1,S1P3, S1P4 and S1P5, thus preventing lymphocyte migration to sites of inflammation bytrapping them within the peripheral lymph nodes, the mesenteric lymph nodes (MLNs) andPeyer's patches. FTY720 has shown great efficacy in both animal models of autoimmunityand human clinical trials and has recently been approved as a first line therapy for multiplesclerosis (MS). However, its clinical use may increase the risk of opportunistic infections,particularly in the gastrointestinal tract. Aims: In this study, we investigated the impact ofFTY720 treatment on an infectious model of colitis, using the enteric pathogen Citrobacterrodentium. Methods: Mice were orally gavaged with vehicle or 3mg/kg FTY720 for 6 dayspre-infection. Mice continued to receive vehicle or FTY720 every 2nd day up until day 12(D12) post-infection. Mice were culled at peak-infection, D8 and at D14 i.e. late infection/clearance. Throughout the study faeces was collected and viable counts enumerated. Atnecropsy, immune cell phenotyping was carried out on cardiac blood by FACS analysis. C.rodentium colonisation was detected using bioluminescent imaging of whole body and exvivo organs. Colons were weighed and measured and samples were taken for qRT-PCR andimmunoflourescent staining. In addition, splenic colony-forming unit (CFU) counts wereenumerated and MLNs were taken for immunoflourescent staining. Results: FACS analysisconfirmed peripheral blood lymphopenia in FTY720-treated animals with reduced numberof T-cells and increased numbers of dendritic cells. Faecal and splenic CFU counts andbioluminescent imaging revealed an inability of the FTY720-treated mice to clear the infectionby D14 in comparison to vehicle-treated animals. These results were supported by clinicaland histological signs of colonic inflammation. Gene expression analysis revealed a deficienthost immune response in drug treated mice evidenced by increased expression of IL-17A andIL-1β and reduced expression of IL-22.Conclusion: Treatment with the immunomodulatorydrug, FTY720, prevents clearance of bacterial infection in the gastrointestinal tract suggestingthat continuous treatment with FTY720 impairs the mucosal immune response.

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Sa1777

NF-κB Regulates Splenomegaly in Response to Bacterial InfectionParthasarathy Chandrakesan, Ishfaq Ahmed, Shahid Umar

Background: The spleen plays an important role in host-protective responses to bacteria.Splenomegaly due to enteric infections has been reported, yet mechanistic explanation islacking. Citrobacter rodentium (CR), a Gram negative bacterium, induces transmissible murinecolonic hyperplasia (TMCH) and variable degrees of inflammation and necrosis dependingupon the genetic background. Aim: To determine if an exaggerated immune axis in responseto CR infection orchestrated by increases in NF-κB activity may regulate splenomegalyduring TMCH. Methodology: TMCH in NIH:Swiss outbred and genetically susceptibleC3H/HeNHsd (C3H) inbred mice was induced by CR infection and standard molecular,biochemical and immunohistochemical techniques were employed. Results: During TMCHin NIH:Swiss mice, we observed gross thickening of the mucosa and significant crypthyperplasia without any splenomegaly at 12 days post-infection. In C3H mice however,breach of intestinal barrier, crypt necrosis and splenomegaly, likely due to accumulation ofimmune cells within the spleen, were common features in 9-day infected animals. CR-infected NIH:Swiss mice failed to exhibit any change in NF-κB activity in the spleen whichcorrelated with lack of splenomegaly in these mice. In C3H mice on the other hand, weobserved a sequential increase in NF-κB activity as early as day 7 post-infection whichpeaked by day 10. This led to dramatic increases in IL-1α/β, IL-12p70, MCP-1, CXCL-1and vascular endothelial growth factor (VEGF) expression. These changes correlated withdramatic decreases in FoxP3 regulatory T-cells and CD11c+ dendritic cells while infiltrationof F4/80+ macrophages and neutrophils increased significantly leading to increases in MPOactivity in the enlarged spleen. We next utilized TLR4-/- mice to determine if NF-κB activationin response to CR infection was mediated via TLR4. CR-infected TLR4-/- mice failed toexhibit either increases in NF-κB activity or spleen size while APCMin/+ mice with intactsplenic TLR4 exhibited significant splenomegaly at 41 days with average size of the spleenreaching three times that of uninfected mice by day 150 following CR infection. DuringCR-infection of T and B-cell deficient Rag-1 (Rag1-/-) mice, splenomegaly was completelyabrogated when compared to wild type littermates. Treatment of CR-infected C3H mice for8 days with diets containing either 6% pectin or 4% bael (Aegle marmelos) extract: i) restoredmucosal integrity, ii) blocked increases in NF-κB activity with subsequent blockade ofIL-1β, IL12p40, MCP-1, CXCL-1, VEGF and MPO activity and, iii) prevented influx ofinflammatory cells to the spleen leading to the restoration of spleen size. Conclusion:Both genetic background and NF-κB-induced changes in VEGF expression and associatedhyperactive immune axis may mechanistically regulate splenomegaly following CR infection.

Sa1778

Comparison of Nitazoxanide and Vancomycin Taper Regimens as a SalvageTherapy for Patients With Recurrent Mild to Moderate Clostridium difficileInfection (CDI)P Patrick Basu, Niraj James Shah, Nithya Krishnaswamy, Chris Tang

Objective: Vancomycin or metronidazole is currently recommend as first-line treatment forCDI with metronidazole preferred for most patients secondary to cost. Anecdotally, manypractitioners report unsatisfactory results with metronidazole and recent studies documentfailure rates up to 50% with the drug. Further data indicates patients with at least twotreatment failures have a 33-65% chance for multiple failures. Vancomycin is consideredthe “gold-standard” treatment for CDI and vancomycin taper dosing has been utilized forrecurrent disease, but concerns of cost, number of doses, and the potential to promotevancomycin resistance to Enterococcus has clinicians seeking new therapies. Nitazoxanidehas demonstrated similar efficacy to vancomycin in a clinical trial and has been reportedto be useful in patients who failed metronidazole therapy. Like vancomycin, nitazoxanideis highly active against CDI, concentrates in the GI tract and has no known In Vitroresistance. The purpose of this study is to compare a novel sequential nitazoxanide regimento vancomycin for the treatment of recurrent CDI. Methods: Thirty (n=30) patients (age:57.9±8.1 years; 13 community acquired and 17 hospital acquired) were treated with oralvancomycin or metronidazole for 14 days and had recurrent CDI within 60 days posttreatment. All patients had abdominal pain, fever, diarrhea >3 times/day, leukocytes >12,000,and positive stool toxin assay for C. difficile toxins A/B. All were randomized into two groups:Group A (n=15) received nitazoxanide 500 mg BID for 14 days, followed by 250 mg BIDfor 7 days, followed by 125 mg BID for 7 days; Group B (n=15) received vancomycin 250mg QID for 14 days, followed by 250 mg BID for 7 days, followed by 125 mg BID for 7days. Exclusion criteria: sepsis, toxic megacolon, inflammatory bowel disease, celiac disease,other colitidies, renal insufficiency, probiotic use, immunocompromized state, hemodialysis,or recent chemotherapy. Results: Stool assays for C. difficile toxins A/B were negative in 10/15 (66.7%) patients after sequential nitazoxanide treatment and in 11/15 (73.3%) patientswith sequential vancomycin therapy. There was no significant difference (p=0.99, Fisher'sexact test) in fecal eradication rate of CDI between the two treatment groups. Both drugswere well tolerated and there were no difference in adverse events between the groups.Conclusion: This novel sequential therapy with nitazoxanide shows a comparable cure rateto sequential oral vancomycin treatment for recurrent CDI. In addition, the nitazoxanideregimen is approximately 25% the cost of the vancomycin regimen with minimal side effects.A larger, double-blinded clinical trial is warranted for validation.

Sa1779

Altered Colonic Metabolite Profile in Active Versus Quiescent UlcerativeColitisVicky De Preter, Greet Vandermeulen, Karen Windey, Severine Vermeire, Paul J.Rutgeerts, Kristin Verbeke

Introduction: Ulcerative colitis (UC) is a chronic relapsing disorder characterized by inflam-mation of the large intestine. Although the aetiology is incompletely understood, the intestinalmicrobiota is generally accepted to play a key role. At present, little is known about themetabolic activity of the microbiota of UC patients and whether metabolites could be related

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