Matthew A. Ciorba, M.D.

Associate Professor
Internal Medicine
Gastroenterology

Molecular Microbiology and Microbial Pathogenesis Program
Immunology Program

  • (314) 273-1808

  • 8124

  • mciorba@WUSTL.EDU

  • https://gastro.wustl.edu/faculty/matthew-ciorba-md/

  • www.ciorbalab.org

  • tryptophan metabolism, intestinal inflammation, colitis associated cancer, colon cancer, mucositis, tryptophan, crohn, colitis, inflammatory bowel disease, radiation enteritis

  • Tryptophan metabolism and probiotic bacteria as modifiers of intestinal cancer and inflammation

Research Abstract:

Our research group is inspired by the challenges endured by patients affected by colon cancer and the inflammatory bowel diseases (IBD, including Crohn’s disease and Ulcerative Colitis). Our guiding goal is to make discoveries that will ultimately enhance quality-of-life for individuals affected by gastrointestinal cancer and intestinal inflammation. To achieve this goal, we are investigating novel ways to therapeutically target disease-related dysfunction of the gut epithelium.

Our research program thrives at the interface of cutting-edge science and personalized medicine. We use innovative basic-translational research approaches and actively engage with the robust clinical programs at WUSM to foster BENCH ↔ BEDSIDE collaboration and discovery. Key techniques include human and murine epithelial stem cell culture (organoids), metabolomics and microbial profiling molecular biology and genetic engineering, assays on tissues samples from patients with IBD and colon cancer as well as murine modeling of IBD and colon cancer.

MAJOR AREAS OF RESEARCH INCLUDE:

Defining how tryptophan metabolism along the kynurenine pathway can be therapeutically targeted in human IBD and colon cancer. We previously identified IDO (Indoleamine 2,3 dioxygenase-1) induction as a strategy to promote tolerance and limit inflammation in models of IBD. We extended this knowledge to two human translational projects examining IDO metabolites as a Crohn’s disease activity biomarker and IDO gene polymorphisms as a predictor of disease severity. More recently, we determined that IDO1 also plays a pathogenic role in promoting progression of colon cancer, an important complication of IBD. Our work indicates that epithelial based tryptophan metabolism in particular is important in disease pathogenesis and developed a new system to test these findings in human derived spheroid cultures. These discoveries formed the platform for our current investigations aimed at defining how to most effectively exploit this “immune checkpoint” pathway to target colitis-associated and sporadic colon cancer.

Defining the role of probiotic bacteria in preventing intestinal mucositis. Defining host-microbial interactions and identifying how these apply to GI health is a major focus of interest in my basic and clinical research. We have specifically focused on the unmet need for strategies to prevent GI toxicity from cytotoxic cancer therapy (intestinal mucositis). We previously demonstrated that exogenous administration of a specific lactobacillus probiotic bacteria, LGG, protects the small intestinal stem cell niche from cytotoxic radiation injury. Work in the lab is currently directed at defining the probiotic derived product that mediates the effect and defining its signaling mechanisms. Additionally, we are exploring ways to enhance this probiotic’s cytoprotective efficacy through dietary manipulation and genetic engineering.

Finally, we are now taking this discovery to cancer patients in need. To do so we developed an IND application with the FDA, navigated regulatory bodies (IRB, NCI cancer center protocol reviews, etc), and initiated an NCI funded Phase 1 clinical trial which is currently enrolling. We anticipate extending these findings to a multi-institutional randomized clinical trial with the Alliance for Clinical Trials in Oncology.

COLLABORATORS
DBBS Laboratory Groups: Thaddeus Stappenbeck, Rodney Newberry, William Stenson, Nicholas Davidson, James Fleckenstein, Phillip Tarr, David Curiel, Dennis Hallahan, Brian Dieckgraefe, Deborah Rubin, Ta-Chiang Liu
Clinical Groups: Gastroenterology, Medical Oncology, Colorectal Surgery, Radiation Oncology

FUNDING FOR OUR RESEARCH (CURRENT OR RECENT):
National Institutes of Health: NIDDK, NCI and NIAID
Crohn’s and Colitis Foundation of America
Longer Life Foundation
www.givinitallforguts.org
Siteman Cancer Center
Central Society for Clinical Research

Selected Publications:

1) VanDussen KL, Marinshaw JM, Shaikh N, Miyoshi H, Moon C, Tarr PI, Ciorba MA*, Stappenbeck TS*. Development of an enhanced human gastrointestinal epithelial culture system to facilitate patient-based assays. Gut 2015;64:911-20. PMID: 25007816 (*Co-corresponding authors)

2) Santhanam S, Alvarado DM, Ciorba MA, Therapeutic targeting of inflammation and tryptophan metabolism in colon and gastrointestinal cancer. Translational Research 2015 Aug 3. pii: S1931-5244(15)00251-0. doi: 10.1016 PMID: 26297050

3) Riehl TE, Santhanam S, Foster L, Ciorba M, Stenson WF. CD44 and TLR4 mediate hyaluronic acid regulation of Lgr5+ stem cell proliferation, crypt fission and intestinal growth in postnatal and adult mice. Am J Physiol Gastrointest Liver Physiol. 2015 Dec 1;309(11):G874-87. doi: 10.1152/ajpgi.00123.2015. Epub 2015 Oct 1 PMID:26505972

4) Lee A, Kanuri N, Zhang Y, Sayuk GS, Li E, Ciorba MA. (2014) IDO1 and IDO2 Non-Synonymous Gene Variants: Correlation with Crohn`s Disease Risk and Clinical Phenotype. PLoS ONE 9(12): e115848.

5) Thaker AI, Rao MS, Bishnupuri KS, Kerr TA, Foster L, Marinshaw JM, Newberry RD, Stenson WF, Ciorba MA. IDO1 Metabolites Activate beta-catenin Signaling to Promote Cancer Cell Proliferation and Colon Tumorigenesis in Mice. Gastroenterology 2013;145:416-425 PMID: 23669411.

6) Ciorba MA*, Riehl TE, Rao MS, Moon C, Ee X, Nava GM, Stappenbeck TS, Stenson WF*. Lactobacillus probiotic protects intestinal epithelium from radiation injury in a TLR-2/cyclo-oxygenase-2-dependent manner. Gut. 2012 Jun;61(6):829-38. PMID: 22027478. (*Co-corresponding authors)

7) Ciorba MA Indoleamine 2,3 dioxygenase in Intestinal Disease. Curr Opin Gastroenterol. 2013 Mar;29(2):146-52. PubMed PMID: 23283180.

8) Packey CD, Ciorba MA. Microbial influences on the small intestinal response to radiation injury. Curr Opin Gastroenterol 2010, 26:88-94. PMID: 20040865

9) Gupta NK, Thaker AI, Kanuri N, Riehl TE, Rowley CW, Stenson WF, Ciorba MA. Serum analysis of tryptophan catabolism pathway: Correlation with Crohn`s disease activity Inflamm Bowel Dis 2012, 18:1214-1220 PMID:21823214

10) Ciorba MA*, Bettonville EE, McDonald KG, Metz R, Prendergast GC, Newberry RD, Stenson WF*. Induction of IDO-1 by immunostimulatory DNA limits severity of experimental colitis. J Immunol. 2010 Apr 1;184(7):3907-16. PMID: 20181893. (*Co-corresponding authors)

Last Updated: 12/8/2017 10:25:38 AM

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