Body fat accumulation and distribution varies across ethnic groups and may influence the prevalence of obesity-related cancers in different ethnicities. This proposal examines the association between adipose accumulation and distribution, the gut microbiome, and phenotypes associated with obesity related cancer risk in the Multi-Ethnic Cohort (MEC). As such, the gut microbiome represents a potentially modifiable obesity-associated factor that may affect cancer risk. The gut microbiome influences human metabolism via regulation of energy uptake from diet, interaction with signaling molecules involved in host fatty acid metabolism, and sub-chronic inflammation~a hallmark of obesity-related diseases. Sub-chronic inflammation may be indirectly mediated through microbially generated dietary metabolites and, directly mediated through activation ofthe innate immune system. For example, gut bacterial endotoxins bind with lipopolysaccharide binding protein (LBP) to Toll-like receptors (TLR) that activate NF 1 levels of cytokines. Variants in human genes related to fatty acid metabolism and innate immunity may alter the interaction of the host with the gut microbiome and alter inflammation associated with obesity-related cancer risk. This innovative project will use the MEC cohort to investigate the composition of the gut microbiome, using high throughput sequencing approaches, as an effect modifier of the relationship between diet, fat distribution, and cancer risk. We will: 1) identify gut microbial profiles associated with body fat amount and distribution in the 5 ethnic groups among the 2,000 MEC subjects re-contacted for this study and analyze 4,229 stool samples collected for the microbiome GWA study in project 2;2) test the associations of these microbial profiles with diet and other lifestyle factors, and with intermediate cancer phenotypes (i.e., cytokines, adipokines, steroid hormones, insulin, IGF hormones, and LBP);3) examine the association between circulating LBP and colorectal cancer, using a case-control study nested within the MEC and measuring LBP in plasma drawn before diagnosis from 1379 colorectal cases and 1379 controls;and 4) participate in analyses integrating the gut microbiome results with those generated in the other projects in order to clarify inter-relationships among variables across data dimensions and construct best predictive models of body fat amount and distribution, and of cancer risk.

Public Health Relevance

The purpose of this grant is to identify the gut bacteria associated with obesity patterns linked to cancer risk. Since the gut bacteria represent potentially modifiable factors associated with obesity, this information could be useful for the intervention/prevention of obesity related cancers

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
5P01CA168530-03
Application #
8729306
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Hawaii
Department
Type
DUNS #
City
Honolulu
State
HI
Country
United States
Zip Code
Citronberg, Jessica S; Wilkens, Lynne R; Lim, Unhee et al. (2016) Reliability of plasma lipopolysaccharide-binding protein (LBP) from repeated measures in healthy adults. Cancer Causes Control 27:1163-6
Utzschneider, Kristina M; Kratz, Mario; Damman, Chris J et al. (2016) Mechanisms Linking the Gut Microbiome and Glucose Metabolism. J Clin Endocrinol Metab 101:1445-54
Fu, Benjamin C; Randolph, Timothy W; Lim, Unhee et al. (2016) Characterization of the gut microbiome in epidemiologic studies: the multiethnic cohort experience. Ann Epidemiol 26:373-9
Setiawan, Veronica Wendy; Lim, Unhee; Lipworth, Loren et al. (2016) Sex and Ethnic Differences in the Association of Obesity With Risk of Hepatocellular Carcinoma. Clin Gastroenterol Hepatol 14:309-16
Hullar, Meredith A J; Fu, Benjamin C (2014) Diet, the gut microbiome, and epigenetics. Cancer J 20:170-5
Sedaghat, Nafiseh; Saegusa, Takumi; Randolph, Timothy et al. (2014) Comparative study of computational methods for reconstructing genetic networks of cancer-related pathways. Cancer Inform 13:55-66
Gathungu, Rose M; Bird, Susan S; Sheldon, Diane P et al. (2014) Identification of metabolites from liquid chromatography-coulometric array detection profiling: gas chromatography-mass spectrometry and refractionation provide essential information orthogonal to LC-MS/microNMR. Anal Biochem 454:23-32
Lim, Unhee; Wilkens, Lynne R; Albright, Cheryl L et al. (2013) University of Hawai'i Cancer Center Connection: bias in self-reported anthropometry in relation to adiposity and adulthood weight gain among postmenopausal Caucasian and Japanese American Women. Hawaii J Med Public Health 72:445-9