Discovery of natural product ovalicin sensitive type 1 methionine aminopeptidases: molecular and structural basis

2019 ◽  
Vol 476 (6) ◽  
pp. 991-1003 ◽  
Author(s):  
Vijaykumar Pillalamarri ◽  
Tarun Arya ◽  
Neshatul Haque ◽  
Sandeep Chowdary Bala ◽  
Anil Kumar Marapaka ◽  
...  
Keyword(s):  
Natural Product ◽  
Active Site ◽  
Covalent Modification ◽  
Structural Basis ◽  
Wild Type ◽  
Methionine Aminopeptidases ◽  
Synthetic Derivative ◽  
Dynamics Simulations

Abstract Natural product ovalicin and its synthetic derivative TNP-470 have been extensively studied for their antiangiogenic property, and the later reached phase 3 clinical trials. They covalently modify the conserved histidine in Type 2 methionine aminopeptidases (MetAPs) at nanomolar concentrations. Even though a similar mechanism is possible in Type 1 human MetAP, it is inhibited only at millimolar concentration. In this study, we have discovered two Type 1 wild-type MetAPs (Streptococcus pneumoniae and Enterococcus faecalis) that are inhibited at low micromolar to nanomolar concentrations and established the molecular mechanism. F309 in the active site of Type 1 human MetAP (HsMetAP1b) seems to be the key to the resistance, while newly identified ovalicin sensitive Type 1 MetAPs have a methionine or isoleucine at this position. Type 2 human MetAP (HsMetAP2) also has isoleucine (I338) in the analogous position. Ovalicin inhibited F309M and F309I mutants of human MetAP1b at low micromolar concentration. Molecular dynamics simulations suggest that ovalicin is not stably placed in the active site of wild-type MetAP1b before the covalent modification. In the case of F309M mutant and human Type 2 MetAP, molecule spends more time in the active site providing time for covalent modification.

scholarly journals Protective Effects of Konjac and Inulin Extracts on Type 1 and Type 2 Diabetes

2019 ◽  
Vol 2019 ◽  
pp. 1-12
Author(s):  
Tianle Gao ◽  
Yue Jiao ◽  
Yang Liu ◽  
Tao Li ◽  
Zhiguo Wang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Blood Glucose ◽  
Dose Group ◽  
Vehicle Control ◽  
Continuous Treatment ◽  
High Risk Population ◽  
Wild Type ◽  
Group A

Objective. The present study was designed to determine whether konjac and inulin extracts or their combination, konjac-inulin (KI) composition, as diet supplementary, can exert beneficial effects against type 1 diabetes and type 2 diabetes using animal models. Methods. A total of 60 diabetic (type 1) rats induced by streptozotocin (STZ) were randomly assigned to five groups: vehicle control (STZ group), KI combination at low dose group (KI-L group), KI combination at medium dose group (KI-M group), KI combination at high dose group (KI-H group), konjac extract group (konjac group), and inulin extract group (inulin group). A sham group (without STZ) was also included. Levels of blood glucose were monitored at each week. After continuous treatment of each diet for 24 days, a glucose tolerance test was performed. After 28 days of treatment, plasma biochemical indicators including glycated serum proteins, total cholesterol, and triglycerides were measured and immunohistochemistry staining of the rat pancreas was performed, to study the insulin expressions. Type 2 diabetes was developed in db/db mice. A total of 28 db/db mice were divided into 4 groups: vehicle control (db/db group), KI composition group (KI group), konjac extract group (konjac group), and inulin extract group (inulin group). A wild-type control group (wild-type group) for db/db mice was also included. Levels of blood glucose, body weight, and blood triglycerides were monitored at each week. Results. Daily use of the KI composition significantly decreased levels of blood glucose and blood triglycerides, as well as improved the insulin production in islets or reduced development of obesity in STZ-induced diabetic rats or in db/db mice. Such effects from KI composition were better than single ingredient of konjac or inulin extract. Conclusion. The results of this study suggest that daily use of KI composition has a protective role on type 1 and 2 diabetes and provided experimental basis for further development of KI composition as a food supplement for diabetic or diabetic high-risk population.

scholarly journals Novel Functions for Glycosyltransferases Jhp0562 and GalT in Lewis Antigen Synthesis and Variation in Helicobacter pylori

2012 ◽  
Vol 80 (4) ◽  
pp. 1593-1605 ◽  
Author(s):  
Mary Ann Pohl ◽  
Sabine Kienesberger ◽  
Martin J. Blaser
Keyword(s):  
Helicobacter Pylori ◽  
Wild Type ◽  
Sequence Analyses ◽  
Upstream Gene ◽  
Content Type ◽  
Lewis Antigen ◽  
Mutant Strains ◽  
H Pylori

ABSTRACTLewis (Le) antigens are fucosylated oligosaccharides present in theHelicobacter pylorilipopolysaccharide. Expression of these antigens is believed to be important forH. pyloricolonization, since Le antigens also are expressed on the gastric epithelia in humans. A galactosyltransferase encoded by β-(1,3)galTis essential for production of type 1 (Leaand Leb) antigens. The upstream genejhp0562, which is present in many but not allH. pyloristrains, is homologous to β-(1,3)galTbut is of unknown function. BecauseH. pyloridemonstrates extensive intragenomic recombination, we hypothesized that these two genes could undergo DNA rearrangement. A PCR screen and subsequent sequence analyses revealed that the two genes can recombine at both the 5′ and 3′ ends. Chimeric β-(1,3)galT-like alleles can restore function in a β-(1,3)galTnull mutant, but neither native nor recombinantjhp0562can. Mutagenesis ofjhp0562revealed that it is essential for synthesis of both type 1 and type 2 Le antigens. Transcriptional analyses of both loci showed β-(1,3)galTexpression in all wild-type (WT) and mutant strains tested, whereasjhp0562was not expressed injhp0562null mutants, as expected. Sincejhp0562unexpectedly displayed functions in both type 1 and type 2 Le synthesis, we asked whethergalT, part of the type 2 synthesis pathway, had analogous functions in type 1 synthesis. Mutagenesis and complementation analysis confirmed thatgalTis essential for Lebproduction. In total, these results demonstrate thatgalTandjhp0562have functions that cross the expected Le synthesis pathways and thatjhp0562provides a substrate for intragenomic recombination to generate diverse Le synthesis enzymes.

scholarly journals Poliomyelitis surveillance in England and Wales, 1969–1975

1978 ◽  
Vol 80 (1) ◽  
pp. 155-167 ◽  
Author(s):  
J. W. G. Smith ◽  
P. J. Wherry
Keyword(s):  
Reproductive Capacity ◽  
Paralytic Poliomyelitis ◽  
Test Results ◽  
Wild Type ◽  
England And Wales ◽  
Marker Test ◽  
Type 3 ◽  
Temperature Test

SUMMARYPoliomyelitis continued to be a rare disease in England and Wales in the period 1969–75. Only 31 paralytic and 44 cases of possible non-paralytic poliomyelitis were recorded during the 7 years.Of the 31 paralytic cases approximately one third were vaccine-associated; 3 were patients who had recently received oral poliovaccine and 7 had been in contact with a vaccinated person. Five of these 7 patients were parents of recently vaccinated children. The rate of vaccine-associated poliomyelitis was estimated in recipients to be 0·2 and in contacts 0·4 per million doses of vaccine given.Marker test results were reported on 555 strains of poliomyelitis virus isolated during 1969–75, using the reproductive capacity temperature test. Forty-eight (8·6%) resembled wild virus in this property, 15 strains being type 1, 8 type 2 and 25 type 3. Most of these isolations of apparently wild virus were from excreters with no symptoms of poliomyelitis, although 3 of the 15 type 1 strains were from patients with paralytic poliomyelitis and 3 from possible cases of non-paralytic poliomyelitis. None of the 8 apparently wild type 2 viruses was from a case of paralytic illness and only 1 of the 39 type 3 strains.Eleven of the 31 paralytic cases were in patients in whom the infection was likely to have been acquired abroad.

scholarly journals Single Channel Function of Inositol 1,4,5-trisphosphate Receptor Type-1 and -2 Isoform Domain-Swap Chimeras

2003 ◽  
Vol 121 (5) ◽  
pp. 399-411 ◽  
Author(s):  
Jorge Ramos ◽  
Wonyong Jung ◽  
Josefina Ramos-Franco ◽  
Gregory A. Mignery ◽  
Michael Fill
Keyword(s):  
Lipid Bilayers ◽  
Single Channel ◽  
Wild Type ◽  
Structural Determinants ◽  
Domain Swap ◽  
Channel Function ◽  
Recombinant Type ◽  
Ligand Regulation

The InsP3R proteins have three recognized domains, the InsP3-binding, regulatory/coupling, and channel domains (Mignery, G.A., and T.C. Südhof. 1990. EMBO J. 9:3893–3898). The InsP3 binding domain and the channel-forming domain are at opposite ends of the protein. Ligand regulation of the channel must involve communication between these different regions of the protein. This communication likely involves the interceding sequence (i.e., the regulatory/coupling domain). The single channel functional attributes of the full-length recombinant type-1, -2, and -3 InsP3R channels have been defined. Here, two type-1/type-2 InsP3R regulatory/coupling domain chimeras were created and their single channel function defined. One chimera (1-2-1) contained the type-2 regulatory/coupling domain in a type-1 backbone. The other chimera (2-1-2) contained the type-1 regulatory/coupling domain in a type-2 backbone. These chimeric proteins were expressed in COS cells, isolated, and then reconstituted in proteoliposomes. The proteoliposomes were incorporated into artificial planar lipid bilayers and the single-channel function of the chimeras defined. The chimeras had permeation properties like that of wild-type channels. The ligand regulatory properties of the chimeras were altered. The InsP3 and Ca2+ regulation had some unique features but also had features in common with wild-type channels. These results suggest that different independent structural determinants govern InsP3R permeation and ligand regulation. It also suggests that ligand regulation is a multideterminant process that involves several different regions of the protein. This study also demonstrates that a chimera approach can be applied to define InsP3R structure-function.

scholarly journals Molecular Dynamics Approach in the Comparison of Wild-Type and Mutant Paraoxonase-1 Apoenzyme Form

2015 ◽  
Vol 9 ◽  
pp. BBI.S25626 ◽  
Author(s):  
Khadija Amine ◽  
Lamia Miri ◽  
Adil Naimi ◽  
Rachid Saile ◽  
Abderrahmane El Kharrim ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Active Site ◽  
Paraoxonase 1 ◽  
Wild Type ◽  
Repetitive Movement ◽  
Catalytic Core ◽  
In The Wild ◽  
Dynamics Simulations ◽  
L1 And L2 ◽  
The Impact

There is some evidence linking the mammalian paraoxonase-1 (PON1) loops (L1 and L2) to an increased flexibility and reactivity of its active site with potential substrates. The aim of this work is to study the structural, dynamical, and functional effects of the most flexible regions close to the active site and to determine the impact of mutations on the protein. For both models, wild-type (PON1wild) and PON1 mutant (PON1mut) models, the L1 loop and Q/R and L/M mutations were constructed using MODELLER software. Molecular dynamics simulations of 20 ns at 300 K on fully modeled PON1wild and PON1mut apoenzyme have been done. Detailed analyses of the root-mean-square deviation and fluctuations, H-bonding pattern, and torsion angles have been performed. The PON1wild results were then compared with those obtained for the PON1mut. Our results show that the active site in the wild-type structure is characterized by two distinct movements of opened and closed conformations of the L1 and L2 loops. The alternating and repetitive movement of loops at specific times is consistent with the presence of 11 defined hydrogen bonds. In the PON1mut, these open-closed movements are therefore totally influenced and repressed by the Q/R and L/M mutations. In fact, these mutations seem to impact the PON1mut active site by directly reducing the catalytic core flexibility, while maintaining a significant mobility of the switch regions delineated by the loops surrounding the active site. The impact of the studied mutations on structure and dynamics proprieties of the protein may subsequently contribute to the loss of both flexibility and activity of the PON1 enzyme.

scholarly journals A Quantitative Ultrastructural Study of Oocytes During the Early Stages of Ovarian Follicular Development in Booroola and Wild-Type Sheep

2021 ◽  
Author(s):  
◽  
Karen Lee Reader
Keyword(s):  
Granulosa Cells ◽  
Follicular Development ◽  
Cell Junctions ◽  
Wild Type ◽  
Cortical Granules ◽  
Surface Areas ◽  
Stage Of Development ◽  
Type 3

<p>In the sheep ovary, primordial follicles are formed as an oocyte surrounded by either a single layer of flattened granulosa cells (type 1) or a mixture of flattened and cuboidal granulosa cells (type 1a). Booroola sheep have a mutation in the growth factor receptor, activin-like kinase receptor 6 (ALK6) which is expressed in oocytes of follicles at the type 1 stage of development. In Booroola ewes homozygous for the ALK6 mutation (BB), oocytes undergo precocious maturation that appears to be initiated during the preantral growth phase. The aim of this study was to quantify the ultrastructural features of oocytes of ovarian follicles at the types 1/1a, 2 and 3 stages of development, from BB and wild-type (++) ewes. Ovaries from 6 ++ and 5 BB 4 week old ewe lambs were processed for both light microscopy (LM) and electron microscopy (EM). LM and stereological methods were used to estimate the mean volume of the oocytes of each follicular type and genotype. EM images and point counting or linear intercept counting were used to estimate the volume of smooth endoplasmic reticulum (SER), Golgi, mitochondria, vesicles, lipid, ribosomes, zona pellucida (ZP) and cortical granules (CG), and the surface area of the outer and inner mictochondrial membranes, microvilli and cell junctions. Oocytes of type 1/1a follicles of BB animals had a greater diameter than that in ++ animals (BB: 29.76 ± 0.58 μm vs ++: 27.05 ± 0.30 μm; P < 0.01) but there were no significant genotype differences in the oocyte diameters of type 2 or 3 follicles. As the follicles of ++ animals developed from the type 1 through to the type 3 stage, the volume and 3 surface areas of all sub-cellular structures measured within oocytes increased (P < 0.05). In oocytes of type 1/1a follicles of BB animals, the SER, mitochondria and ZP volumes were greater than in ++ animals (P < 0.05) as were the surface areas of the outer mitochondrial membranes, oocyte membrane, and zonula adherens type junctions (P < 0.05). At the type 2 stage of development the lipid volume was greater in oocytes of ++ animals, and at the type 3 stage of development the ribosomal volume was greater in oocytes of BB animals. These results suggest that the ALK6 mutation in BB animals has influenced the ultrastructural properties of oocytes in the type 1/1a follicle. This early genotype difference in follicular characteristics may influence the rate of follicular development during the early developmental stages.</p>

scholarly journals Molecular determinant of substrate binding and specificity of cytochrome P450 2J2

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Liang Xu ◽  
Liao Y. Chen
Keyword(s):  
Arachidonic Acid ◽  
Cytochrome P450 ◽  
Active Site ◽  
Structural Model ◽  
Substrate Binding ◽  
Conformational Dynamics ◽  
Structural Basis ◽  
Molecular Determinant ◽  
Dynamics Simulations

AbstractCytochrome P450 2J2 (CYP2J2) is responsible for the epoxidation of endogenous arachidonic acid, and is involved in the metabolism of exogenous drugs. To date, no crystal structure of CYP2J2 is available, and the proposed structural basis for the substrate recognition and specificity in CYP2J2 varies with the structural models developed using different computational protocols. In this study, we developed a new structural model of CYP2J2, and explored its sensitivity to substrate binding by molecular dynamics simulations of the interactions with chemically similar fluorescent probes. Our results showed that the induced-fit binding of these probes led to the preferred active poses ready for the catalysis by CYP2J2. Divergent conformational dynamics of CYP2J2 due to the binding of each probe were observed. However, a stable hydrophobic clamp composed of residues I127, F310, A311, V380, and I487 was identified to restrict any substrate access to the active site of CYP2J2. Molecular docking of a series of compounds including amiodarone, astemizole, danazol, ebastine, ketoconazole, terfenadine, terfenadone, and arachidonic acid to CYP2J2 confirmed the role of those residues in determining substrate binding and specificity of CYP2J2. In addition to the flexibility of CYP2J2, the present work also identified other factors such as electrostatic potential in the vicinity of the active site, and substrate strain energy and property that have implications for the interpretation of CYP2J2 metabolism.

Human Factor VIIai(K62E) Is a More Effective Inhibitor of Coagulation Than Wild-Type FVIIai.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1949-1949
Author(s):  
Bryan J. Clarke ◽  
Sampath Sridhara ◽  
Morris A. Blajchman
Keyword(s):  
Conformational Change ◽  
Active Site ◽  
Relative Increase ◽  
Competitive Elisa ◽  
Covalent Modification ◽  
Cell Surface Receptor ◽  
Factor Vii ◽  
Wild Type ◽  
Clotting Time ◽  
Molar Excess

Abstract Background: In previous work we provided evidence for a linked conformational change of the recombinant factor VII(rFVII) first epidermal growth factor-like(EGF1) domain associated with chloromethylketone(ck) covalent modification of the wild-type(WT) rFVIIa active site (J Biol Chem275:34894,2000). All naturally-occurring mutations of the human FVII gene hitherto described encode plasma FVII with both reduced activity and affinity for their cell-surface receptor tissue factor (TF). We have recently characterized a mutant rFVII protein, rFVIIa(K62E), which has both increased enzymatic activity and a 5-fold greater affinity for TF than wild-type rFVIIa (J Thromb Haemost3:1250, 2005). In the present report we provide data about the TF-binding characteristics and conformational state of rFVIIa(K62E) before and after inactivation with a variety of chloromethylketones. Methods: Purification of both the rFVIIa(K62E) mutant protein and rFVIIa(WT) and their ck-inactivated derivatives was achieved by anion-exchange chromatography. FVII antigen concentration was determined by ELISA and biological activity by modified prothrombin time (PT) assay. Affinity of inactivated rFVIIa(rFVIIai) for both TF and a FVII EGF1 domain conformation-specific monoclonal antibody(Moab 231–7) was determined by competitive ELISA (IC50). Results: The affinity of rFVIIai(K62E)DEGR and rFVIIai(K62E)FFR for TF were increased 24.4-fold and 7.7-fold respectively versus rFVIIa(WT)[shown below]. Notably, the enhanced affinity of both rFVIIai(K62E) and unmodified rFVIIa(K62E) for TF was associated with substantially increased affinity for Moab 231–7 as compared to rFVIIa(WT). The clotting time of diluted human plasma was significantly more prolonged by rFVIIai(K62E)DEGR and rFVIIai(K62E)FFR than rFVIIai(WT). Comparison of rFVIIai(K62E) and rFVIIai(WT) rFVIIa Preparation Affinity for TF(IC50) Relative Increase in TF Affinity Relative Increase in Affinity for Moab 231–7 Prolongation of Plasma Clotting time(sec) Reduction of Coagulant Activity(%) Affinity of rFVII for TF (IC50 expressed as molar excess of rFVII) was determined by competitive ELISA. Plasma clotting times were determined at 2.5-fold molar excess of each rFVIIai inhibitor. Control plasma clotting time was 81 sec. rFVIIai(K62E)DEGR 0.13 24.4 3.1 68 90 rFVIIai(K62E)FFR 0.41 7.7 4.9 57 86 rFVIIa(K62E) 0.46 6.9 4.1 ND ND rFVIIai(WT)DEGR 0.98 3.2 3.5 1 4 rFVIIai(WT)FFR 0.62 5.1 1.2 27 65 rFVIIa(WT) 3.17 1 1 ND ND Conclusions: We provide evidence that both active-site modification and the substitution K→E in human rFVIIa(K62E) causes conformational change(s) within the FVII EGF1 domain associated with a substantially increased affinity of rFVIIa(K62E) and rFVIIai(K62E) for TF. Both rFVIIai(K62E)DEGR and rFVIIai(K62E)FFR show considerable promise as more effective inhibitors of coagulation than rFVIIai(WT).

scholarly journals RAGE Mediates Cholesterol Efflux Impairment in Macrophages Caused by Human Advanced Glycated Albumin

2020 ◽  
Vol 21 (19) ◽  
pp. 7265
Author(s):  
Adriana Machado-Lima ◽  
Raquel López-Díez ◽  
Rodrigo Tallada Iborra ◽  
Raphael de Souza Pinto ◽  
Gurdip Daffu ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Glycated Albumin ◽  
Wild Type ◽  
Intracellular Lipid ◽  
Glycation End Products ◽  
Macrophage Cholesterol Efflux ◽  
Cellular Cholesterol Efflux

We addressed the involvement of the receptor for advanced glycation end products (RAGE) in the impairment of the cellular cholesterol efflux elicited by glycated albumin. Albumin was isolated from type 1 (DM1) and type 2 (DM2) diabetes mellitus (HbA1c > 9%) and non-DM subjects (C). Moreover, albumin was glycated in vitro (AGE-albumin). Macrophages from Ager null and wild-type (WT) mice, or THP-1 transfected with siRNA-AGER, were treated with C, DM1, DM2, non-glycated or AGE-albumin. The cholesterol efflux was reduced in WT cells exposed to DM1 or DM2 albumin as compared to C, and the intracellular lipid content was increased. These events were not observed in Ager null cells, in which the cholesterol efflux and lipid staining were, respectively, higher and lower when compared to WT cells. In WT, Ager, Nox4 and Nfkb1, mRNA increased and Scd1 and Abcg1 diminished after treatment with DM1 and DM2 albumin. In Ager null cells treated with DM-albumin, Nox4, Scd1 and Nfkb1 were reduced and Jak2 and Abcg1 increased. In AGER-silenced THP-1, NOX4 and SCD1 mRNA were reduced and JAK2 and ABCG1 were increased even after treatment with AGE or DM-albumin. RAGE mediates the deleterious effects of AGE-albumin in macrophage cholesterol efflux.

2 EFFECTS OF AN IBD-ASSOCIATED MICROBIAL COMMUNITY STATE ON INTESTINAL INFLAMMATION IN HUMANIZED GNOTOBIOTIC MICE

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S40-S40
Author(s):  
Venu Lagishetty ◽  
Nerea Arias ◽  
Tien Dong ◽  
Meg Hauer ◽  
William Katzka ◽  
...  
Keyword(s):  
Microbial Community ◽  
Intestinal Inflammation ◽  
Fecal Microbiota ◽  
Wild Type ◽  
Microbial Composition ◽  
Germ Free ◽  
First Degree Relatives ◽  
Gnotobiotic Mice

Abstract Background and Aims We previously reported that 20% of unaffected first-degree relatives of pediatric IBD patients share the same microbial community structure (OTU-type) as IBD patients. This suggests that a preexisting dysbiosis can predispose to the development of IBD. The aims of this study were to establish that microbial community types identified in the family cohort could be reconstituted in gnotobiotic mice for further translational studies and to assess for any direct effects of this microbiota on intestinal inflammation. Methods Over 100 germ-free wild-type C57/BL6 mice were colonized for 4 weeks in the UCLA gnotobiotic facility with fecal microbiota from 30 human donors belonging to each of four groups from the pediatric family cohort: unaffected first-degree relatives with OTU-type 1, unaffected first-degree relatives with the IBD-associated OTU-type 2, Crohn’s disease (CD) with OTU-type 1, CD with OTU-type 2. Each group was represented by 8 human donors (n=3–4 mice/donor) with the exception of CD OTU-type 1 (only 5 donors available in the cohort). In addition, 35 eight week old germ-free IL-10-/- C57/BL6 mice were colonized for 12 weeks with fecal microbiota from 4 CD OTU-type 2 donors and 4 unaffected OTU-type 1 donors (n=4–5/donor). Luminal and mucosal microbial composition in the colon and small intestine was evaluated by 16S rRNA sequencing. Intestinal inflammation was assessed in the small intestine and colon by semiquantitative scoring of H&E stained sections. Results Donor-specific microbial composition was observed in the humanized gnotobiotic mice with clear separation between recipients of donor OTU-type 1 vs. OTU-type 2 stool. Parallel differences in differentially abundant microbes and microbial diversity were seen in these gnotobiotic mice as in the original human donors. No histologic evidence was found for colitis, enteritis, or fibrosis in wild-type colonized mice. However, fecal lipocalin was increased two-fold increase in recipients of OTU-type 2 microbiota from CD patients relative to the other three groups. CD humanized IL-10-/- mice exhibited lower microbial diversity and distinct microbial composition compared to non-IBD humanized IL-10-/- mice, mirroring differences in the human donors. Mice colonized with CD microbiota had increased histological disease severity in the colon and cecum (p=0.05) compared to mice colonized with non-IBD microbiota. Conclusion Our results demonstrate that human microbial community states identified in the pediatric IBD cohort could be reconstituted in gnotobiotic mice for translational studies. Moreover, CD-associated dysbiosis exacerbated colitis severity. These data support the concept that dysbiosis plays a direct role in promoting intestinal inflammation and provide an experimental framework for further mechanistic studies of IBD-associated microbial communities.

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