Gut pathogen virulence and its therapeutic modulation during surgical injury

我们在小鼠和危重病人身上证明，在手术损伤/感染后，肠道

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.