The unfortunate combination of genetic background and colonization by certain inciting commensal bacteria, can result in the development of inflammatory bowel diseases (IBD) in genetically susceptible individuals. Because little can be done presently to correct genetic susceptibility, changing the gut flora of IBD patients in a predictable and sustainable way represents a tangible and practical solution. We believe this can be accomplished through dietary manipulation of the enteric microbiota. Two hypotheses will be tested: (1) that certain dietary fats which that are well represented in """"""""Western diets"""""""" ar capable of either precipitating or preventing/ameliorating colonic inflammation through their actions on the enteric microbiome (Aim 1), and (2) that dietary intervention with fatty acid supplements or increased short chain fatty acid bioavailability can reshape disease-causing enteric microbiomes to reduce risk or ameliorate IBD, thus setting the stage for future clinical application. We show, for instance, that risk for developing colitis in IL-10 KO mice can be significantly increased by diets high in saturated, milk-derived fat, which promote the bloom of immunogenic Deltaproteobacteria that are part of the """"""""rare biosphere"""""""" of the enteric microbiome. We also show that several forms of dietary supplementation can reshape and alter the immunogenicity of saturated fat-induced changes in the enteric microbiota. These studies will take advantage of cultivation-dependent and -independent approaches and the bioinformatic analysis services of DDRCC Host-Microbe Core. In addition, microbiota transfer and gnotobiotic animal technologies will be used to determine if there is causal role of diet-induced changes of the enteric microbiota in creating immune imbalances and adverse risk outcomes. In summary, we will determine how diet affects and can be used to manipulate the enteric microbiota to restore immune homeostasis and reduce risk and severity of complex immune-mediated disorders. The knowledge gained through these studies will provide fundamental insights into the cause of IBD and help define dietary strategies to prevent or ameliorate IBD through manipulation of the enteric microbiota.

Public Health Relevance

We will investigate how specific dietary fats affect the composition of the intestinal microbes and what impact this has on host immune balance, health and development of IBD in genetically susceptible mice. We will also examine how certain dietary supplements can reshape disease-promoting gut microbial profiles to restore and maintain health. By doing so, we can develop effective and practical measures that can be used clinically to prevent and treat inflammatory bowel diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK097268-02
Application #
8549226
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (04))
Program Officer
Grey, Michael J
Project Start
2012-09-25
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$406,961
Indirect Cost
$140,994
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Cason, Cori A; Dolan, Kyle T; Sharma, Gaurav et al. (2018) Plasma microbiome-modulated indole- and phenyl-derived metabolites associate with advanced atherosclerosis and postoperative outcomes. J Vasc Surg 68:1552-1562.e7
Martinez-Guryn, Kristina; Hubert, Nathaniel; Frazier, Katya et al. (2018) Small Intestine Microbiota Regulate Host Digestive and Absorptive Adaptive Responses to Dietary Lipids. Cell Host Microbe 23:458-469.e5
Pierre, Joseph F; Hinterleitner, Reinhard; Bouziat, Romain et al. (2018) Dietary antioxidant micronutrients alter mucosal inflammatory risk in a murine model of genetic and microbial susceptibility. J Nutr Biochem 54:95-104
Nobutani, Kentaro; Miyoshi, Jun; Musch, Mark W et al. (2017) Daikenchuto (TU-100) alters murine hepatic and intestinal drug metabolizing enzymes in an in vivo dietary model: effects of gender and withdrawal. Pharmacol Res Perspect 5:
Touw, Ketrija; Ringus, Daina L; Hubert, Nathaniel et al. (2017) Mutual reinforcement of pathophysiological host-microbe interactions in intestinal stasis models. Physiol Rep 5:
Dolan, Kyle T; Chang, Eugene B (2017) Diet, gut microbes, and the pathogenesis of inflammatory bowel diseases. Mol Nutr Food Res 61:
Martinez, Kristina B; Leone, Vanessa; Chang, Eugene B (2017) Western diets, gut dysbiosis, and metabolic diseases: Are they linked? Gut Microbes 8:130-142
Martinez, Kristina B; Leone, Vanessa; Chang, Eugene B (2017) Microbial metabolites in health and disease: Navigating the unknown in search of function. J Biol Chem 292:8553-8559
Miyoshi, Jun; Chang, Eugene B (2017) The gut microbiota and inflammatory bowel diseases. Transl Res 179:38-48
Hasebe, Takumu; Matsukawa, Jun; Ringus, Daina et al. (2017) Daikenchuto (TU-100) Suppresses Tumor Development in the Azoxymethane and APCmin/+ Mouse Models of Experimental Colon Cancer. Phytother Res 31:90-99

Showing the most recent 10 out of 41 publications