Colorectal cancer (CRC) is the second most common cause of cancer-related mortality in developed countries. Chronic gastrointestinal (GI) inflammation, as occurs in inflammatory bowel disease (IBD), is one of the primary risk factors for the development of colorectal cancer. Recent evidence suggests that the complex community of bacteria present in the GI tract (gut microbiota; GM) has a tremendous impact on host health, particularly in diseases such as IBD and CRC. Additionally, there is evidence that the GM of healthy individuals can be clustered into a limited number of distinct compositions called enterotypes. The impact of these various enterotypes on disease risk is unknown. One particular bacterial species (segmented filamentous bacteria; SFB) has recently gained considerable attention due to its myriad effects on the mucosal immune system and an apparent correlation with ulcerative colitis, one form of IBD. Notably however, the methodologies needed to adequately characterize the largely uncultivable bacteria present in the GM have not existed long enough to track humans longitudinally from the time prior to disease development to the point at which CRC is diagnosed. Thus, existing data on the role of the GM in CRC are correlative and do not demonstrate a causal relationship. Additionally, the GM is acquired beginning at birth and does not normalize to its stable adult composition until some point in childhood or early adolescence. It is unknown whether the risk of CRC later in life is determined during the initial colonization of the gut, or if disease risk can be modulated later in life throuh changes in the GM. The proposed studies will answer these questions through the use of a mouse model with distinct similarities to the human condition. In this model, CRC is induced in mice carrying a genetic mutation affecting a pathway implicated in the development of human CRC. Disease is initiated via experimental inoculation with a weakly opportunistic pathogen shown to induce host immune responses to other non-pathogenic, commensal bacteria, thus mimicking the environment present in individuals at high risk of CRC such as those diagnosed with IBD. This model will allow disease to be tracked longitudinally through all stages of disease development, and will allow for the controlled, prospective assessment of experimental treatments. While the specific microbes present in the GM of humans and mice differ, there are highly conserved functional properties of higher microbial taxa, e.g., family or class. Thus, data generated in the proposed studies will be translatable to humans and will direct the design of subsequent experiments. Moreover, metabolomic profiling will serve to identify differences between individuals that do or do not progress to CRC, in the function of the GM. Of note, these findings will inform the development of both diagnostic and therapeutic modalities for use in humans and could have far-reaching consequences in the fields of oncology and gastroenterology.

Public Health Relevance

There is accumulating evidence that the complex community of bacteria present in the gut may modulate the risk of developing colorectal cancer. The proposed studies will examine the composition of the gut bacterial community in individuals that do or do not progress to colorectal cancer, and will provide data amenable to use in the development of novel diagnostic assays and therapies.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01OD019924-05
Application #
9908196
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Fuchs, Bruce
Project Start
2016-02-01
Project End
2020-12-31
Budget Start
2020-01-01
Budget End
2020-12-31
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Missouri-Columbia
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
Hart, Marcia L; Ericsson, Aaron C; Lloyd, K C Kent et al. (2018) Development of outbred CD1 mouse colonies with distinct standardized gut microbiota profiles for use in complex microbiota targeted studies. Sci Rep 8:10107
Montonye, Dan R; Ericsson, Aaron C; Busi, Susheel B et al. (2018) Acclimation and Institutionalization of the Mouse Microbiota Following Transportation. Front Microbiol 9:1085
Johnson, Philip J; Hargreaves, Leeza L; Zobrist, Chelsea N et al. (2018) Utility of a portable desiccant system for preservation of fecal samples for downstream 16S rRNA amplicon sequencing. J Microbiol Methods 146:1-6
Haney, Megan M; Ericsson, Aaron C; Lever, Teresa E (2018) Effects of Intraoperative Vagal Nerve Stimulation on the Gastrointestinal Microbiome in a Mouse Model of Amyotrophic Lateral Sclerosis. Comp Med :
Miller, Craig; Abdo, Zaid; Ericsson, Aaron et al. (2018) Applications of the FIV Model to Study HIV Pathogenesis. Viruses 10:
Seamons, Audrey; Treuting, Piper M; Meeker, Stacey et al. (2018) Obstructive Lymphangitis Precedes Colitis in Murine Norovirus-Infected Stat1-Deficient Mice. Am J Pathol 188:1536-1554
Ericsson, Aaron C; Gagliardi, Jonalyn; Bouhan, Delia et al. (2018) The influence of caging, bedding, and diet on the composition of the microbiota in different regions of the mouse gut. Sci Rep 8:4065
Bidot, Willie A; Ericsson, Aaron C; Franklin, Craig L (2018) Effects of water decontamination methods and bedding material on the gut microbiota. PLoS One 13:e0198305
Boynton, Felicia D Duke; Ericsson, Aaron C; Uchihashi, Mayu et al. (2017) Doxycycline induces dysbiosis in female C57BL/6NCrl mice. BMC Res Notes 10:644
Ericsson, Aaron C; Personett, Alexa R; Turner, Giedre et al. (2017) Variable Colonization after Reciprocal Fecal Microbiota Transfer between Mice with Low and High Richness Microbiota. Front Microbiol 8:196

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