The central goal of this proposal is to understand molecular mechanisms of probiosis for new treatment and prevention strategies in inflammatory bowel disease. This proposal includes comprehensive genetic and peptidomic approaches in order to determine the molecular basis of anti-inflammatory functions by probiotics. Our laboratory has obtained evidence for novel mechanisms of probiosis including inhibition of pro-inflammatory TNFa production by macrophages. Intestinal lactobacilli have been isolated and tested for tumor necrosis factor-alpha (TNF-a)-inhibitory activity. The overall hypothesis is that probiotic intestinal Lactobacillus strains secrete peptides that suppress TNF-a signaling in macrophages and inhibit intestinal inflammation. The functions of candidate Lactobacillus genes that regulate probiotic activities including peptide secretion will be studied in vitro using macrophages activated by Toll-like receptor agonists. Wild type lactobacilli and knockout Lactobacillus strains lacking anti-inflammatory effects in vitro will be administered to IL-10-deficient mice in order to explore mechanisms of probiotic action in vivo. Identification of probiotic genes encoding anti-inflammatory functions and probiotic response pathways in macrophages may provide valuable insights into potential human targets for probiotic action in Crohn's disease. 1. Specify probiotic anti-inflammatory genes in intestinal Lactobacillus strains by knockout mutagenesis. 2. Identify anti-inflammatory glutamate-containing peptides by comparative peptidomics of the Lactobacillus secretome. 3. Compare mucosal inflammatory responses in the intestines of IL-10-deficient mice colonized with knockout or wild type isogenic strains of probiotic Lactobacillus. These studies will facilitate the identification of beneficial bacteria that can be used to treat inflammatory bowel disease such as Crohn's disease and ulcerative colitis. We seek to understand the mechanisms of action of beneficial intestinal bacteria so that new strains can be identified naturally or engineered for human medicine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK065075-03
Application #
7564082
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Hamilton, Frank A
Project Start
2007-02-01
Project End
2011-01-31
Budget Start
2009-02-01
Budget End
2010-01-31
Support Year
3
Fiscal Year
2009
Total Cost
$336,058
Indirect Cost
Name
Baylor College of Medicine
Department
Pathology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Engevik, Melinda A; Versalovic, James (2017) Biochemical Features of Beneficial Microbes: Foundations for Therapeutic Microbiology. Microbiol Spectr 5:
Pokusaeva, K; Johnson, C; Luk, B et al. (2017) GABA-producing Bifidobacterium dentium modulates visceral sensitivity in the intestine. Neurogastroenterol Motil 29:
Gao, Chunxu; Ganesh, Bhanu Priya; Shi, Zhongcheng et al. (2017) Gut Microbe-Mediated Suppression of Inflammation-Associated Colon Carcinogenesis by Luminal Histamine Production. Am J Pathol 187:2323-2336
Davidovics, Zev H; Carter, Beth A; Luna, Ruth Ann et al. (2016) The Fecal Microbiome in Pediatric Patients With Short Bowel Syndrome. JPEN J Parenter Enteral Nutr 40:1106-1113
Thomas, Carissa M; Saulnier, Delphine M A; Spinler, Jennifer K et al. (2016) FolC2-mediated folate metabolism contributes to suppression of inflammation by probiotic Lactobacillus reuteri. Microbiologyopen 5:802-818
Boonma, Prapaporn; Spinler, Jennifer K; Venable, Susan F et al. (2014) Lactobacillus rhamnosus L34 and Lactobacillus casei L39 suppress Clostridium difficile-induced IL-8 production by colonic epithelial cells. BMC Microbiol 14:177
Hemarajata, P; Spinler, J K; Balderas, M A et al. (2014) Identification of a proton-chloride antiporter (EriC) by Himar1 transposon mutagenesis in Lactobacillus reuteri and its role in histamine production. Antonie Van Leeuwenhoek 105:579-92
Whary, Mark T; Muthupalani, Sureshkumar; Ge, Zhongming et al. (2014) Helminth co-infection in Helicobacter pylori infected INS-GAS mice attenuates gastric premalignant lesions of epithelial dysplasia and glandular atrophy and preserves colonization resistance of the stomach to lower bowel microbiota. Microbes Infect 16:345-55
Devaraj, Sridevi; Hemarajata, Peera; Versalovic, James (2013) The human gut microbiome and body metabolism: implications for obesity and diabetes. Clin Chem 59:617-28
Hemarajata, P; Gao, C; Pflughoeft, K J et al. (2013) Lactobacillus reuteri-specific immunoregulatory gene rsiR modulates histamine production and immunomodulation by Lactobacillus reuteri. J Bacteriol 195:5567-76

Showing the most recent 10 out of 32 publications