The ability to translate pre-clinical findings into viable therapeutic options in humans is a significant challenge. Recent work investigating the human microbiome has demonstrated that microbial communities that exist within and upon our bodies play a large role in health and disease. The microbiota that is harbored in the intestinal tract, due in large part to the vast number and diversity of microbes in the gut, plays the most crucial role in human health. Therefore, there has been a recent push to develop microbial-based therapeutics for the treatment of intestinal disease. The main function of the Therapeutic Probiotic Optimization Core is to provide Projects 1 and 2 with microbial-based therapeutics that will ameliorate intestinal GVHD. Objective 1 of the core is to isolate novel intestinal bacteria capable of producing high levels of butyrate and that also possess anti-inflammatory properties. We have developed human fecal bioreactors that allow for the generation of complex microbial communities and moderate throughput testing of bacteria that produce butyrate. Core 2 will provide Project 1 with complex communities that produce high levels of butyrate for testing. Objective 2 of the core is to develop probiotic Lactobacillus reuteri into a therapeutic delivery vehicle to provide IL- 22, REG3A and Reg3? directly to the intestinal tract. Preliminary data demonstrates that L.reuteri can secrete active IL-22 and REG3A. Advances in our basic understanding of the microbiome have set the stage for more detailed characterizations of the functional properties and metagenomic differences between health and disease. In the context of BMT and GVHD, several studies have characterized broad differences between the gut microbiota of BMT patients before and during GVHD. These studies demonstrate a loss of microbial diversity and an increase Enterococci in during GVHD. To further understand the pathogenesis of GVHD, it is critical to decipher the mechanisms by which specific strains in a microbiota mediate GVHD. The lack of consistent, well-characterized microbiotas in GVHD studies represents a major confounding factor that could differentiate patients at risk for severe GVHD. Over the past five years, the laboratory of Dr. Faith, the new director of Core 2, has developed high-throughput microbial isolation pipelines, high-throughput gnotobiotic community screening technologies, and efficient computational algorithms to identify specific microbial strains that modulate host physiology. With these microbial culture isolation methods, the Core has access to a biobank of microbial culture collections with over 600 strains isolated from 14 individuals. We are therefore in a unique position to use the tools and reagents to understand the influence of diverse microbial communities on intestinal pathogenesis in experimental GVHD models. Identification of the specific microbial strains that drive or prevent GVHD will enable mechanistic studies of disease etiology and facilitate development of innovative therapeutics for GVHD patients. One highly innovative approach to new therapeutics for GVHD leverages the therapeutic potential of microbes. The production of short chain fatty acids via fermentation by anaerobes in the colon can have profound effects on the host, and high levels of butyrate stimulate Treg cell expansion in the gut. Over the past five years the laboratory of Dr. Britton has isolated several hundred microorganisms from the human gut and screened them for their ability to produce butyrate and other short chain fatty acids. Using in vitro bioreactors Core 2 has isolated and characterized bacterial strains with potential therapeutic benefit in GVHD. In addition, advances in the precision genome engineering of gut bacteria and the ability to apply synthetic biology technology to strain development has made the delivery of human therapeutic proteins via bacteria a reality. Lactobacillus reuteri is associated with many mammalian intestinal tracts and has co-evolved with host species throughout evolution. We have developed a human strain of L.reuteri as a therapeutic delivery vehicle that can survive transit through the human intestinal tract and inserted human genes into the genome without antibiotic selection.
CORE 2 NARRATIVE The microbiota represents a complex system of interacting organisms, which collectively or individually can influence health. Culture independent 16S rDNA amplicon sequencing provides an established tool to characterize these ecosystems and correlate changes in the ecosystem with health. Gnotobiotic animals, colonized with specific microbial taxa, provide a platform to control and understand this complex system, enabling causative identifications of microbes that modulate host physiology. In this microbiome core, we will combine our expertise and gnotobiotics, 16S rDNA amplicon sequencing, and high throughput microbial isolation to identify specific human gut microbes that modulate GVHD in animal models.
|Holtan, Shernan G; DeFor, Todd E; Panoskaltsis-Mortari, Angela et al. (2018) Amphiregulin modifies the Minnesota Acute Graft-versus-Host Disease Risk Score: results from BMT CTN 0302/0802. Blood Adv 2:1882-1888|
|Ortiz-Velez, Laura; Ortiz-Villalobos, Javiera; Schulman, Abby et al. (2018) Genome alterations associated with improved transformation efficiency in Lactobacillus reuteri. Microb Cell Fact 17:138|
|Ferrara, James L M; Chaudhry, Mohammed S (2018) GVHD: biology matters. Hematology Am Soc Hematol Educ Program 2018:221-227|
|Major-Monfried, Hannah; Renteria, Anne S; Pawarode, Attaphol et al. (2018) MAGIC biomarkers predict long-term outcomes for steroid-resistant acute GVHD. Blood 131:2846-2855|
|Naymagon, Steven; Naymagon, Leonard; Wong, Serre-Yu et al. (2017) Acute graft-versus-host disease of the gut: considerations for the gastroenterologist. Nat Rev Gastroenterol Hepatol 14:711-726|
|Hartwell, Matthew J; Özbek, Umut; Holler, Ernst et al. (2017) An early-biomarker algorithm predicts lethal graft-versus-host disease and survival. JCI Insight 2:e89798|
|Stickel, N; Hanke, K; Marschner, D et al. (2017) MicroRNA-146a reduces MHC-II expression via targeting JAK/STAT signaling in dendritic cells after stem cell transplantation. Leukemia 31:2732-2741|
|Ferrara, James Lm; Smith, Christopher M; Sheets, Julia et al. (2017) Altered homeostatic regulation of innate and adaptive immunity in lower gastrointestinal tract GVHD pathogenesis. J Clin Invest 127:2441-2451|
|Miller, Holly K; Braun, Thomas M; Stillwell, Terri et al. (2017) Infectious Risk after Allogeneic Hematopoietic Cell Transplantation Complicated by Acute Graft-versus-Host Disease. Biol Blood Marrow Transplant 23:522-528|
|Renteria, Anne S; Levine, John E; Ferrara, James L M (2016) Therapeutic targets and emerging treatment options in gastrointestinal acute graft-versus-host disease. Expert Opin Orphan Drugs 4:469-484|
Showing the most recent 10 out of 231 publications