The foregut is constantly barraged with flora contaminating ingested substances. In order to ensure that digestion and absorption of nutrients is unimpeded, bacterial replications must be limited until the cecum is reached. Although the 'gastric acid barrier'effectively reduces bacterial counts in the stomach, many bacterial species can escape this barrier. Thus, additional defenses are in place to eradicate organisms resistant to gastric acid/pepsin. The most described secondary defenses include the antimicrobial peptides such as the defensins and cryptidins. Here, we describe for the first time in mammalian tissue, the function of surface oxidases, termed dual oxidase or DUOX, in the control of foregut bacterial colonization. Although these oxidases have been implicated in airway defense, and have been studied in drosophila and C. elegans intestine, there is no published report of their function in the mammalian gut. On the basis of our preliminary data and literature publications, we have formulated a hypothesis regarding how foregut bacteria activates DUOX through pattern recognition receptor (PRR) sensing, ATP signalling, purinoreceptor activation, and (Ca++)i increase, with H2O2 secreted into the lumen, which combined with secreted SCN- to form the strong oxidant, microbicidal anion OSCN-. This regulated system, for the secretion of microbicidal substances, which I will term the 'DUOX system', is likely to be an important foregut defense system against bacterial colonization with important pathogens. We propose to study Duox and PRR in the perfused anesthetized, rat and mouse intestine, measuring peroxide, ATP, and other released substances with standard assays. Knockout mice, when available, will be used to examine to function of individual components of the system. Since Duox is hypothesized to control foregut bacterial colonization, the proposed system may bear on several important diseases, such as small intestinal bacteria overgrowth (SIBO), cystic fibrosis, and inflammatory bowel disease.

Public Health Relevance

The proposed research, in which we intend to study how peroxide secreted by the intestine kills bacteria, bears on many important diseases that place a large burden on society. In particular, inflammatory bowel disease, irritable bowel syndrome, and cystic fibrosis are all diseases, all currently incurable, in which colonization with the wrong kind of bacteria can be causative. Malfunction of the peroxide-based antimicrobial system may be an important reason why these diseases cause so much tissue injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK054221-14A1
Application #
8438218
Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
Program Officer
Carrington, Jill L
Project Start
1999-05-01
Project End
2017-03-31
Budget Start
2013-04-10
Budget End
2014-03-31
Support Year
14
Fiscal Year
2013
Total Cost
$295,727
Indirect Cost
$46,037
Name
Brentwood Biomedical Research Institute
Department
Type
DUNS #
197170756
City
Los Angeles
State
CA
Country
United States
Zip Code
90073
Kaji, Izumi; Akiba, Yasutada; Konno, Kohtarou et al. (2016) Neural FFA3 activation inversely regulates anion secretion evoked by nicotinic ACh receptor activation in rat proximal colon. J Physiol 594:3339-52
Kaunitz, Jonathan D (2016) The Doppler Effect: A Century from Red Shift to Red Spot. Dig Dis Sci 61:340-1
Said, Hyder; Kaji, Izumi; Kaunitz, Jonathan D (2015) Gastroduodenal mucosal defense mechanisms. Curr Opin Gastroenterol 31:486-91
Kaji, Izumi; Iwanaga, Toshihiko; Watanabe, Masahiko et al. (2015) SCFA transport in rat duodenum. Am J Physiol Gastrointest Liver Physiol 308:G188-97
Akiba, Yasutada; Kaunitz, Jonathan D; Million, Mulugeta (2015) Peripheral corticotropin-releasing factor receptor type 2 activation increases colonic blood flow through nitric oxide pathway in rats. Dig Dis Sci 60:858-67
Akiba, Yasutada; Inoue, Takuya; Kaji, Izumi et al. (2015) Short-chain fatty acid sensing in rat duodenum. J Physiol 593:585-99
Fujiwara, Kaori; Inoue, Takuya; Yorifuji, Naoki et al. (2015) Combined treatment with dipeptidyl peptidase 4 (DPP4) inhibitor sitagliptin and elemental diets reduced indomethacin-induced intestinal injury in rats via the increase of mucosal glucagon-like peptide-2 concentration. J Clin Biochem Nutr 56:155-62
Sakanaka, Taisuke; Inoue, Takuya; Yorifuji, Naoki et al. (2015) The effects of a TGR5 agonist and a dipeptidyl peptidase IV inhibitor on dextran sulfate sodium-induced colitis in mice. J Gastroenterol Hepatol 30 Suppl 1:60-5
Kaunitz, Andrew M; Kaunitz, Jonathan D (2015) Compounded bioidentical hormone therapy: time for a reality check? Menopause 22:919-20
Kaji, I; Akiba, Y; Said, H et al. (2015) Luminal 5-HT stimulates colonic bicarbonate secretion in rats. Br J Pharmacol 172:4655-70

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