2.1. SCIENTIFIC RATIONALE. Wide global variation in age standardized rates of colorectal cancer (CRC) of 1.2 to 45.0/100,000 largely reflect the impact of dietary and lifestyle factors in the etiology of the disease.''The influence of the environment on CRC is evidenced by the change in CRC rates among 1st- and 2nd-generation immigrants to that of the host country, regardless of genetic background. Dietary and other lifestyle effects on the gut microbiome have long been postulated to explain these population differences in CRC rates. With recent advances in sequencing technology, it is now clear that diet and lifestyle (e.g., smoking, obesity, physical activity) significantly influence the composition of the gut microflora with findings from experimental models and humans providing solid evidence for link between gut microbiota and CRC.[3-6] These findings has revitalized interest in the contribution of gut microbiota to CRC with particular interest in how the gut microbiome disturbs normal tissue homeostasis to enhance susceptibility to CRC as prevention targets.[3-6] A long-standing interest of the UACC group is the role of bile acids (BA) and CRC. BAs, particularly the secondary BAs, are strongly suspect in CRC etiology.[7-8] Secondary BAs are produced by intestinal bacteria to salvage BAs that escape transport in the distal ileum. These excess BAs act as substrates for intestinal bacterial dependent deconjugation of the hydroxy groups at C-3, C-7 and C-12 and 7alpha/Beta-dehydroxylation.[9-10] These bacteria-dependent processes give rise to suspected carcinogens: deoxycholic acid (DCA) and lithocholic acid (LCA). Our preliminary data suggest that the composition of the gut flora influences the composition of fecal BAs;which we postulate influences individual risk of neoplasia in the colorectum. In this proposal our primary hypothesis is that lifestyle, diet, and health status impact the functional component of the gut microbiome and that these factors collectively influence the colonic BA composition as a risk factor for CRC. Our secondary hypothesis is that the effect(s) of shared environmental factors on the functional component of the gut microbiome that leads to production of pro-tumorigenic fecal BAs is largely independent of race/ethnicity and reflects the sharing of environmental factors. In our studies of colorectal adenoma (CRA) (i.e., the premalignant precursor for CRC), minority populations are grossly underrepresented. As such, a major limitation of our studies is our inability to generalize findings on CRC risk factors and intervention targets to populations relevant to Arizona including Native Americans (NA). For NAs, a major challenge is the relatively small size of the population. The low population density, relative to non-Hispanic White (NHW), is a major factor in their underrepresentation. One strategy to assess the relative importance of our findings from NHW to the NA community is to test whether relationships between diet and the gut microbiome on fecal BA composition observed in NHW are similar in NA;particularly any found to be strongly associated with the risk of CRC. As part of our planned efforts described in the specific aims below, we will also initiate and effort to test if relationships observed between BAs (pro or anti-tumorigenic) and the gut microbiota and CRA identified in Aims 1 and 2 in NHWs are also present in NA populations. 2.2. SCIENTIFIC AIMS S.1 In cross-section (baseline only), determine the association between the gut microbiome and the fecal BA composition in 735 participants of a Phase III trial to prevent CRA, considering the effects of age, sex, diet, and other factors (e.g., smoking, obesity, race/ethnicity and diabetes). S.2 Test if baseline gut microbiome composition is associated with development of CRA and whether any association between the gut microbiome and CRA is dependent on baseline fecal BA composition, considering the intervention with ursodeoxycholic acid (UDCA). S.3 Characterize differences in the gut microbiome and BA compositions in rural and urban dwelling Navajo and relate the findings to those observed in the study of NHWs at risk of CRC. The training component of this aim is for mentee Dr Yellowhair [mentored by Dr Thompson] to lead an effort to describe the gut microbiome and BA composition and levels in Navajo, considering urbanization, age, sex, and lifestyle (diet and exercise). 2.3 IMPACT. Identification of the factors (BAs, gut microbiome) that mediate the role of the environment in CRC will allow us to better target and modify the physiological factors that underlie the elevated CRC risk that occurs with modern diet and lifestyle factors. Further, demonstration of shared physiological consequences across NHW and NA populations would vastly enhance our ability to extrapolate findings from one population to another.
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