Gut pathogen virulence and its therapeutic modulation during surgical injury
Gut pathogen virulence and its therapeutic modulation during surgical injury
批准号:
10384951
负责人:
John C Alverdy
金额:
$48.38万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2001
资助国家:
美国
项目状态:
未结题
起止时间:
2001-02-01 至 2026-03-31
关键词:
AddressAdverse effectsAntibiotic ResistanceAntibioticsBackBindingBone MarrowButyratesCancer BiologyCecumCoculture TechniquesCommunicable DiseasesConsumptionCouplingCritical IllnessDataDoctor of PhilosophyExposure toFamilyFecesFundingGene ExpressionGoalsHealthHepatectomyHistonesHumanImmunologyImpairmentIndolesInfectionInflammationInjuryInstitutesLaboratoriesLibrariesLinkMetabolismModelingMolecularMusOperative Surgical ProceduresPancreatitisPathogenicityPatientsPatternPeritoneumPeritonitisPhenotypePlayProcessProductionRecoveryResistanceResolutionRoleSerratia marcescensStressStructureSurgical InjuriesSurgical ModelsTestingTherapeuticTimeTryptophanVirulenceVirulentWorkanticancer researchbaseclinically relevantglobal healthgut microbiomegut microbiotaimmune functionimprovedin vivomacrophagemicrobialmicrobiomemicrobiome alterationmicrobiome researchmicrobiotamicrobiota metabolitesmid-career facultymortalitymouse modelnutritionpathogenpressureprofessorprogramsrestorationsurgery outcomewestern diet
中文摘要
我们在小鼠和危重病人身上证明,在手术损伤/感染后,肠道
英文摘要
1 We demonstrated in both mice and critically ill humans, that following surgical injury/infection, the gut
2 microbiota collapse in structure, membership and function (i.e., production of health-relevant metabolites) such
3 that both immune function and host recovery is impaired. In this proposal we seek to identify those metabolites
4 produced by the gut microbiota that play a key and causal role in determining the outcome from surgical
5 injury/infection via their ability to program macrophages such that they eliminate pathogens and resolve
6 inflammation with proper timing and coordination. We show, for the first time that gut microbiome-derived
7 metabolites (i.e., butyrate, indoles and others) can shift macrophages from the M1 to the M2 phenotype
8 leading to recovery from potentially lethal surgical infection (i.e., S. marcescens peritonitis). Work from our
9 collaborator (Lev Becker, PhD) recently described a “timer mechanism” by which key metabolites (i.e. lactate
10 and others) accumulate within macrophages, bind to histones and drive homeostatic gene expression so they
11 properly transition from M1 (pathogen elimination) to M2 (inflammation resolution). Therefore we will test the
12 hypothesis that recovery from surgical injury/infection is dependent on gut microbiome-generated
13 metabolites that program macrophages to clear pathogens and resolve inflammation in a properly
14 timed and regulated manner. Understanding the molecular details in this process will uncover a yet unknown
15 mechanism by which maintaining a healthy gut microbiome following surgical injury/infection enhances
16 survival. Therefore, in this proposal we will address the following specific aims:
17 Aim 1: Define the relationship between the gut microbiota, the metabolites it produces and their
18 effects on macrophage phenotypes that predicts recovery from surgical infection.
19 Aim2: Determine the composition of gut microbiome metabolites that activate macrophages co-
20 cultured with S. marcescens to express a survival-related phenotype and define the mechanisms
21 involved.
22 Aim 3: Enrich the mouse gut with select microbial consortia that are high producers of survival-
23 related gut metabolites and determine the mechanisms by which they enhance macrophage function
24 and survival following surgical injury/infection.
25 We are currently working with two world class experts in the field of immunology and microbiome sciences to
26 carry out the proposed studies and have already generated exciting and compelling preliminary data. These
27 include Dr Lev Becker, Associate Professor of Ben May Department of Cancer Research Committee on
28 Cancer Biology and the Committee on Molecular Metabolism and Nutrition and Dr Eric Pamer, Section of
29 Infectious Diseases and Global Health, Donald F. Steiner Professor; Director, The Duchossois Family Institute.
30 The work herein proposed is mechanistic, generalizable and highly translatable to surgical injury and infection.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
A novel, non-antibiotic, microbiome-directed agent to prevent post-surgical infection
-
批准号:10600765
-
项目类别:
-
资助金额:$29.91万
-
财政年份:2023
-
负责人:John C Alverdy
-
依托单位:
Serial Endoscopic Surveillance (SES) and Direct Topical Antibiotics (DTA) to prev
-
批准号:8756542
-
项目类别:
-
资助金额:$15.84万
-
财政年份:2014
-
负责人:John C Alverdy
-
依托单位:
Interplay of diet and the metabolome in establishment of the juvenile gut microbi
-
批准号:8458113
-
项目类别:
-
资助金额:$23.66万
-
财政年份:2012
-
负责人:John C Alverdy
-
依托单位:
Interplay of diet and the metabolome in establishment of the juvenile gut microbi
-
批准号:8282260
-
项目类别:
-
资助金额:$21.12万
-
财政年份:2012
-
负责人:John C Alverdy
-
依托单位:
GASTRIC BYPASS EFFECTS ON SLEEP & GLUCOSE REG
-
批准号:7378613
-
项目类别:
-
资助金额:$1.05万
-
财政年份:2006
-
负责人:John C Alverdy
-
依托单位:
GASTRIC BYPASS EFFECTS ON SLEEP & GLUCOSE REG
-
批准号:7201011
-
项目类别:
-
资助金额:$2.91万
-
财政年份:2005
-
负责人:John C Alverdy
-
依托单位:
Gastric bypass effects on sleep & glucose reg
-
批准号:7040709
-
项目类别:
-
资助金额:$13.72万
-
财政年份:2004
-
负责人:John C Alverdy
-
依托单位:
PSEUDOMONAS' EFFECTS ON THE GUT BARRIER FROM SURGERY
-
批准号:6570142
-
项目类别:
-
资助金额:$3.34万
-
财政年份:2001
-
负责人:John C Alverdy
-
依托单位:
PSEUDOMONAS' EFFECTS ON THE GUT BARRIER FROM SURGERY
-
批准号:6628941
-
项目类别:
-
资助金额:$25.07万
-
财政年份:2001
-
负责人:John C Alverdy
-
依托单位:
Pseudomonas' effects on the gut barrier from surgery
-
批准号:7337799
-
项目类别:
-
资助金额:$1.29万
-
财政年份:2001
-
负责人:John C Alverdy
-
依托单位:
Pseudomonas' effects on the gut barrier from surgery
-
批准号:7192565
-
项目类别:
-
资助金额:$36.28万
-
财政年份:2001
-
负责人:John C Alverdy
-
依托单位:
Pseudomonas' effects on the gut barrier from surgery
-
批准号:6922670
-
项目类别:
-
资助金额:$31.64万
-
财政年份:2001
-
负责人:John C Alverdy
-
依托单位:
Pseudomonas' effects on the gut barrier from surgery
-
批准号:7451227
-
项目类别:
-
资助金额:$0.77万
-
财政年份:2001
-
负责人:John C Alverdy
-
依托单位:
PSEUDOMONAS' EFFECTS ON THE GUT BARRIER FROM SURGERY
-
批准号:6498868
-
项目类别:
-
资助金额:$24.97万
-
财政年份:2001
-
负责人:John C Alverdy
-
依托单位:
Pseudomonas' effects on the gut barrier from surgery
-
批准号:7653040
-
项目类别:
-
资助金额:$39.0万
-
财政年份:2001
-
负责人:John C Alverdy
-
依托单位:
Gut pathogen virulence and its therapeutic modulation during surgical injury
-
批准号:10393947
-
项目类别:
-
资助金额:$1.14万
-
财政年份:2001
-
负责人:John C Alverdy
-
依托单位:
PSEUDOMONAS' EFFECTS ON THE GUT BARRIER FROM SURGERY
-
批准号:6608389
-
项目类别:
-
资助金额:$1.0万
-
财政年份:2001
-
负责人:John C Alverdy
-
依托单位:
PSEUDOMONAS' EFFECTS ON THE GUT BARRIER FROM SURGERY
-
批准号:6229434
-
项目类别:
-
资助金额:$24.98万
-
财政年份:2001
-
负责人:John C Alverdy
-
依托单位:
Pseudomonas' effects on the gut barrier from surgery
-
批准号:8319495
-
项目类别:
-
资助金额:$36.42万
-
财政年份:2001
-
负责人:John C Alverdy
-
依托单位:
Gut pathogen virulence and its therapeutic modulation during surgical injury
-
批准号:9900002
-
项目类别:
-
资助金额:$45.06万
-
财政年份:2001
-
负责人:John C Alverdy
-
依托单位:
海外基金