Dr. Wilson is a graduate of the College of Arts and Sciences at Cornell University in Ithaca, NY, where he was in the College Scholar Honors Program. He received his M.D. from Harvard Medical School. He completed residency in Internal Medicine at Case Western Reserve University Hospitals, followed by Fellowship in Gastroenterology at University of Chicago Medical Center, where he was an NIH T32 trainee and recipient of a Research Fellowship Award from the Crohn’s & Colitis Foundation of America (CCFA). He was then recruited to University of Maryland School of Medicine as an Assistant Professor, and was promoted to Associate Professor with tenure. He was able to secure funding from the CCFA, followed by NIH K08 and R01 funding and a VA Merit Review. He served as the Gastroenterology Section Chief at the Baltimore VA Medical Center from 2002-2005. He moved to Vanderbilt University Medical Center in 2005 as Professor of Medicine, where he was recruited to build a mucosal immunology research program.
Keith T. Wilson, M.D. holds the Thomas F. Frist Sr. Chair in Medicine, and is Professor of Medicine, Cancer Biology, and Pathology, Microbiology and Immunology at Vanderbilt University School of Medicine. He is a physician-scientist in the area of Gastrointestinal Research. He is a Staff Physician at the VA Tennessee Valley Healthcare System in Nashville, where he does endoscopy and GI consults. He is the Director of Research in the Division of Gastroenterology, Hepatology and Nutrition and formerly was the Director of the GI Fellowship Program from 2005 to 2015.
His research is focused on GI inflammation and carcinogenesis, with studies investigating both Helicobacter pylori-associated immune dysregulation and gastric cancer development and Inflammatory Bowel Disease. The work in his laboratory related to polyamines in gastric carcinogenesis has led to a clinical trial in Latin America in which an inhibitor of polyamine synthesis, difluoromethylornithine (DFMO, eflornithine) is being used in human subjects with gastric precancerous lesions. Dr. Wilson is the Founding Director of the Vanderbilt CMIC. He holds multiple grants from NIH and the Department of Veterans Affairs. He is the Associate Director of the Vanderbilt Digestive Disease Research Center, funded by an NIH P30 grant, where he directs the Pilot and Feasibility Grant Program. He is also the Director of the Digestive Disease Research component of the NIH T35-funded Summer Research Training Program and he has mentored over 100 trainees. He has presented the work from his laboratory at numerous international meetings, including the Keynote Lecture at the 2016 American Society for Oncology GI Cancer Symposium. He has been elected as the 2017 Vice Chair and 2019 Chair of the Gordon Research Conference on Polyamines.
Research Interests
My laboratory is focused on gastrointestinal mucosal inflammation and carcinogenesis. We study the host immune response to the gastric pathogen Helicobacter pylori that causes peptic ulcer disease and gastric cancer. This includes the innate immune response in macrophages and the identification of ways that this response is ineffective. We have also elucidated mechanisms whereby epithelial responses are inappropriate, leading to risk for cancer development. We study novel mechanisms for inflammation and cellular/DNA damage, which leads to increased cancer risk. We have reported that H. pylori induces the enzyme spermine oxidase (SMOX), which utilizes the polyamine spermine as substrate. Generation of H2O2 by SMOX results in apoptosis of macrophages due to mitochondrial membrane depolarization. Spermine itself contributes to the inadequacy of the host response, by blocking translation of inducible nitric oxide (NO) synthase (iNOS) and hence NO production that is needed for the killing of H. pylori. SMOX causes oxidative stress in gastric epithelial cells that leads to both apoptosis and DNA damage. Induction of ornithine decarboxylase (ODC) that generates polyamines also leads to apoptosis of macrophages, contributing to loss of host innate immunity to H. pylori. We recently reported that myeloid-specific knockout of Odc leads to increased immune activation and inflammation in the mouse H. pylori infection model. Another recent discovery in our lab was that epidermal growth factor receptor (EGFR) phosphorylation is an important part of the host response to activating stimuli, such as H. pylori or the colitis-inducing bacterium, Citrobacter rodentium, in macrophages. Mice with myeloid-specific deletion of EGFR exhibited decreased H. pylori-induced gastritis, C. rodentium-induced colitis, and less tumors in the AOM-DSS model of colitis-associated carcinogenesis. Further, we also reported that an EGFR inhibitor given in the food markedly attenuated gastric carcinoma development in the mouse INS-GAS and gerbil models of H. pylori-induced cancer. We are extensively utilizing clinical material from cohorts of human subjects from Colombia and Central America, where H. pylori infection prevalence is very high, but gastric cancer risk is much higher in the mountains when compared to the coastal regions. Our studies implicated the polyamine-driven oxidative stress and associated DNA damage. Work showing that an inhibitor of polyamide synthesis reduced gastric inflammation and cancer in rodents led to a clinical trial that we are conducting with this agent (difluoromethylornithine) in human subjects with precancerous gastric lesions. We are also pursuing studies on immune dysregulation in inflammatory bowel disease. This includes work on arginine availability/transport, polyamines, nitric oxide. and the micro biome. We have reported that levels of the amino acid L-arginine are decreased in the tissues of humans with ulcerative colitis. Because L-arginine is important in regulation of epithelial integrity and immune function a defect in the utilization of L-arginine could contribute to the disease pathogenesis. Consistent with this, we have shown that treatment with L-arginine improves colitis in mouse models. Further, mice lacking an inducible L-arginine transporter have increased disease activity in the DSS injury model but reduced colitis in the C. rodentium infection model. We are investigating alterations in the microbiome as a potential contributor to these differences. Our funded studies are focused on: 1) Mechanisms of H. pylori induced immune dysregulation, arginine metabolism in the immune response and disease progression (PI, VA Merit Review Grant) 2) Oxidative stress and EGFR activation in the development of gastric cancer in Colombia, and the importance of H. pylori strains from regions of low and high gastric cancer risk in modulation of host responses (PI, P01 grant) 3) Role of EGFR signaling and polyamines in epithelial dysfunction in H. pylori infection and carcinogenesis (PI, project on second P01) 4) Inhibition of polyamine synthesis with difluoromethylornithine in human subjects in Colombia and Honduras with precancerous gastric lesions (PI, R01 grant). 5) Arginine and other amino acids as immunomodulatory agents and potential therapies in colitis and colitis-associated cancer (PI, R01 grant)