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           A major focus of our investigations are on a specific enzyme, Indoleamine 2,3 Dioxygenase (IDO), which has been demonstrated to have potent immune modulating capacity.  Using experimental models and other laboratory-based approaches we have identified IDO as an important regulator of the intestinal inflammatory response and as modifier of colitis-associated cancer progression.  IDO expression is increased in both human IBD and colitis models.  Blocking this enzyme worsens inflammation, while pharmacologic upregulation of intestinal IDO expression limits inflammation.  Our investigations show that targeting of IDO may have therapeutic potential in both colitis, and colitis associated cancer.  This work is and has been supported by the NIH/NIDDK and the Crohn’s and Colitis Foundation of America. 

          We are also working to define 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.

          Additionally, we are working to define 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.

Selected Publications

For a Pubmed search, click here.​​

© 2018 Ciorba Lab

Major areas of research

Research


       All of our research efforts are directed at improving the length and quality of life for patients affected by inflammatory conditions of the gastrointestinal tract.  Along with our colleagues, we have used clinical databases and laboratory modeling to study the general fields of intestinal inflammation, injury repair, and carcinogenesis.  Our work is inspired by clinical interactions with patients affected by the human inflammatory bowel diseases, and those patients who experience significant gastrointestinal side effects from radiotherapy induced bowel injury.   The overarching goal of our research is to identify novel ways to improve life for patients enduring these illnesses.  Translating our findings to human relevance is aided by our Division’s DDRCC clinical database, and BioSpecimens repository.

        A separate focus of the lab is to explore the role and mechanisms by which probiotic bacteria protect the intestinal epithelium from radiation injury.  The small intestine is highly sensitive to radiation and is a major site of injury during radiation therapy.  Diarrhea as a side effect is the limiting factor in dosing radiation therapy for rectal cancer and other abdominal malignancies.  There is a need for agents that could be given before radiation therapy to diminish radiation injury to the small intestine, without decreasing the radiation sensitivity of the tumor.  Our research suggests that certain lactobacillus probiotics or their probiotic-derived products may be useful as a prophylactic strategy to limit intestinal injury to humans during radiation therapy.  Initial funding for this work came from the inaugural Global Probiotic Council’s Young Investigator Award.  We developed and are now initiating a randomized clinical trial to extend this work to humans.  This work is supported by the Longer Life Foundationand a grant from the Siteman cancer center.

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. 2014 Jul.


Iskandar HI, Cassell B, Kanuri N, Gyawali CP, Guttierrez A, Dassopoulos T, Ciorba MA*, Sayuk GS*. Tricyclic Antidepressants for Management of Residual Symptoms in Inflammatory Bowel. J Clin Gastroeneterol. Accepted (* Co-corresponding authors)

Ciorba MA. Kynurenine pathway metabolites: relevant to vitamin B-6 deficiency and beyond. Am J Clin Nutr. 2013 Oct;98(4):863-4.

Thaker AI, Rao MS, Bishnupuri KS, Kerr TA, Foster L, Marinshaw JM, Newberry RD, Stenson WF, Ciorba MA. IDO1 metabolites activate β-catenin signaling to promote cancer cell proliferation and colon tumorigenesis in mice. Gastroenterology. 2013 Aug;145(2):416-25.e1-4. 

Ciorba MA. Indoleamine 2,3 dioxygenase in intestinal disease. Curr Opin Gastroenterol. 2013 Mar;29(2):146-52.

Thaker AI, Shaker A, Rao MS, Ciorba MA. Modeling Colitis-Associated Cancer with Azoxymethane (AOM) and Dextran Sulfate Sodium (DSS). J Vis Exp. 2012 Sep 11.

Iskandar HN,
Ciorba MA. Biomarkers in inflammatory bowel disease: current practices and recent advances. Transl Res. 2012 Apr
.

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 Jul.

Ciorba MA, Riehl TE, Rao MS, Moon C, Ee X, Nava GM, Walker MR, Marinshaw JM, StappenbeckTS, Stenson WF. Lactobacillus probiotic protects intestinal epithelium from radiation injury in a TLR-2/cyclo-oxygenase-2-dependent manner. Gut. 2012 Jun.

Ciorba MA. A Gastroenterologist's Guide to Probiotics. Clin Gastroenterol Hepatol. 2012 Sep.

Ha CY, Kumar N, Raptis CA, Narra VR,
Ciorba MA. Magnetic resonance enterography: safe and effective imaging for stricturing Crohn's disease. Dig Dis Sci. 2011 Oct.

Chen H, Lee A, Bowcock A, Zhu W, Li E, Ciorba M, Hunt S. Influence of Crohn's disease risk alleles and smoking on disease location. Dis Colon Rectum. 2011 Aug.

Williams MD, Ha CY, Ciorba MA: Probiotics as therapy in gastroenterology: a study of physician opinions and recommendations. J Clin Gastroenterol 2010, 44:631-636.

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

Ha CY, Newberry RD, Stone CD,
Ciorba MA. Patients with late-adult-onset ulcerative colitis have better outcomes than those with early onset disease. Clin Gastroenterol Hepatol. 2010 Aug.

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.

Ciorba MA, Stenson WF. Probiotic therapy in radiation-induced intestinal injury and repair. Ann N Y Acad Sci. 2009 May.

Ciorba MA, Prakash C. Wireless capsule endoscopy in the diagnosis of small bowel Crohn's disease. Inflamm Bowel Dis. 2003 Jul.