Department of Medicine
7309 Biomolecular Bldg
microbial/mucosal immune responses determining mucosal homeostasis vs inflammation
Dr. Sartor is a physician scientist, board-certified gastroenterologist with expertise in managing difficult-to-treat patients with inflammatory bowel diseases (IBD) and a mucosal immunologist/microbiologist with a long-term interest in understanding mechanisms by which resident microbiota induce chronic intestinal inflammation vs. mucosal homeostasis. His lab develops and studies rodent models of chronic, immune-mediated intestinal inflammation relevant to IBD and performs clinically relevant translational studies involving IBD patients. He investigates genetically-determined immune responses to luminal resident microbial components using gnotobiotic mice and patient-derived samples, and studies the influence of environmental factors on intestinal microbiota composition and function. He has published over 400 articles, editorials, and chapters, edited 5 books, and have been continuously funded by the NIH (NIDDK) since 1983. In 2020, Dr. Sartor received the AGA’s Basic Science Achievement Award, recognizing his career-long contributions to understanding the role of the gut microbiota in intestinal inflammation and homeostasis
His research showed an essential role of resident enteric bacteria in inducing and maintaining enterocolitis, first in gnotobiotic HLA-B27 transgenic rats, then later in IL10 knockout mice and multiple other genetically engineered mouse models. He was the first to demonstrate the differential ability of individual resident bacterial species to induce colitis in monoassociated genetically susceptible hosts, different phenotypes of colitis in individual hosts colonized by two different bacterial species, differential host susceptibility to different bacterial species and differential ability of functionally altered bacterial strains to induce colitis in susceptible hosts. He demonstrated an important effect of inflammation on enteric bacterial gene expression and explored functional effects of specific bacterial genes by monoassociating IL10-/- mice with deletion mutants of several colitogenic enteric bacterial species. His hypothesis that IBD, particularly Crohn’s disease, is a result of overly aggressive T cell-mediated immune responses to a subset of resident microbiota in a genetically susceptible host is now widely accepted as the most likely driving force of IBD. He was one of the early investigators of cytokines and inflammatory mediators in the pathogenesis of IBD and mucosal homeostasis. Dr. Sartor demonstrated the relative expression of pro- and anti-inflammatory cytokines, kallikrein-kinin, IGF, and growth hormone in experimental colitis and performed the first PCR measurements of cytokines in mucosal biopsies of IBD patients. He used recombinant IL-1 receptor antagonists and IL-10 to inhibit chronic experimental enterocolitis and arthritis in rodent models and demonstrated a key role for cyclooxygenase 1 and 2 in mucosal homeostasis. More recently he has investigated the differential ability of various resident microbiota species to stimulate protective immune responses in normal hosts, observing that IL-10 secreted by antigen-presenting cells in response to resident microbiota is a key determinant of mucosal protection against chronic inflammation by inducing regulatory T cells. These observations have been extended to IL-10-secreting regulatory B cells that activate IL-10-producing regulatory T cells (TR1) to prevent microbial-induced chronic intestinal inflammation. He has shown that resident microbiota activate IL-10-producing colonic lamina propria in regulatory B cells in a TLR2/MyD88/PI3K-dependent manner. Recently we have demonstrated that rationally designed live biotherapeutic bacteria consortia can prevent and treat experimental colitis in humanized murine colitis models.
Mishima Y, Oka A, Liu B, Herzog JW, Eun CS, Fan TJ, Bulik-Sullivan E, Carroll IM, Hansen JJ, Chen L, Wilson JE, Fisher NC, Ting JP, Nochi T, Wahl A, Garcia JV, Karp CL, Sartor RB. Microbiota maintain colonic homeostasis by activating TLR2/MyD88/PI3K signaling in IL-10-producing regulatory B cells. J Clin Invest. 2019 Jun 18;129(9):3702-3716. doi: 10.1172/JCI93820. PMID: 31211700; PMCID: PMC6715367.
Guo H, Chou WC, Lai Y, Liang K, Tam JW, Brickey WJ, Chen L, Montgomery ND, Li X, Bohannon LM, Sung AD, Chao NJ, Peled JU, Gomes ALC, van den Brink MRM, French MJ, Macintyre AN, Sempowski GD, Tan X, Sartor RB, Lu K, Ting JPY. Multi-omics analyses of radiation survivors identify radioprotective microbes and metabolites. Science. 2020 Oct 30;370(6516):eaay9097. doi: 10.1126/science.aay9097. PMID: 33122357; PMCID: PMC7898465.
Liu R, Kang JD, Sartor RB, Sikaroodi M, Fagan A, Gavis EA, Zhou H, Hylemon PB, Herzog JW, Li X, Lippman RH, Gonzalez-Maeso J, Wade JB, Ghosh S, Gurley E, Gillevet PM, Bajaj JS. Neuroinflammation in Murine Cirrhosis Is Dependent on the Gut Microbiome and Is Attenuated by Fecal Transplant. Hepatology. 2020 Feb;71(2):611-626. doi: 10.1002/hep.30827. Epub 2019 Aug 19. PMID: 31220352; PMCID: PMC6923631.
van der Lelie D, Oka A, Taghavi S, Umeno J, Fan TJ, Merrell KE, Watson SD, Ouellette L, Liu B, Awoniyi M, Lai Y, Chi L, Lu K, Henry CS, Sartor RB. Rationally designed bacterial consortia to treat chronic immune-mediated colitis and restore intestinal homeostasis. Nat Commun. 2021 May 28;12(1):3105. doi: 10.1038/s41467-021-23460-x. PMID: 34050144; PMCID: PMC8163890.