The gastrointestinal microbiome forms a "bridge" between diet, mammalian metabolism, and immunity. Gut microbes can modulate innate and adaptive immune responses in the gut via different signaling pathways, and suppression of inflammation may alter predisposition to cancer, specifically colorectal neoplasms. Bacterial genes in the microbiome encode for enzymes that perform biochemical conversion of dietary amino acids into various microbial metabolites. We propose that amino acid metabolites derived from the human microbiome suppress neoplasia by inhibiting mucosal inflammation and cell proliferation. Based on recent findings, intestinal bacteria can convert amino acids, such as L-histidine, into biogenic amines, such as histamine, that suppress pro-inflammatory cytokine production by impeding MAP kinase signaling. Several L-histidine metabolites have demonstrated immunomodulatory effects and raise the possibility that luminal conversion by gut microbes may be an important strategy for diet-mediated cancer prevention. The overall hypothesis is that L-histidine metabolites produced by gut microbes, including but not limited to histamine, suppress chronic intestinal inflammation and inflammation-associated colonic neoplasia by regulating Stat3 and MAP kinase signaling pathways.
In Aim 1, suppression of acute intestinal inflammation by L-histidine metabolites of the human gut microbiome will be explored. Bacterial strains with potent immunomodulatory and histidine-metabolizing activities have been isolated from the human microbiome. L-histidine pathways and metabolites will be explored by gene expression and metabolomics studies of gut lactobacilli. Endowment of the mouse gut microbiome with histidine-metabolizing, histamine-generating genes from the human microbiome will facilitate studies of the interplay between diet and the intestinal microbiome in vivo.
In Aims 2 and 3, two different mouse models (DSS-ApcMin/+ and Hdc-/-) will be used to explore the importance of L-histidine metabolism and histamine generation in the biology of chronic intestinal inflammation and colorectal cancer. Isotopically labeled L-histidine will be deployed as a tracer to explore gut microbiome- mediated amino acid metabolism in vivo. These studies may point the way towards an improved understanding of how diet and the microbiome affect cancer risk in human populations.

Public Health Relevance

This project seeks to understand how gut bacteria in the human microbiome may convert amino acids in the diet into chemical compounds (metabolites) that suppress the immune system and inflammation in the intestine. By studying natural gut bacteria that normally live in the healthy human intestine, we hope to understand how bacteria may also prevent cancers associated with chronic inflammation. Discoveries from these experiments could lead to new microbiome-based strategies to prevent or treat colorectal and other human cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA170930-02
Application #
8711382
Study Section
Special Emphasis Panel (ZCA1-SRLB-Y (M2))
Program Officer
Flores, Roberto L
Project Start
2013-08-01
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
2
Fiscal Year
2014
Total Cost
$597,078
Indirect Cost
$130,640
Name
Baylor College of Medicine
Department
Pathology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Boonma, Prapaporn; Spinler, Jennifer K; Venable, Susan F et al. (2014) Lactobacillus rhamnosus L34 and Lactobacillus casei L39 suppress Clostridium difficile-induced IL-8 production by colonic epithelial cells. BMC Microbiol 14:177
Spinler, Jennifer K; Sontakke, Amrita; Hollister, Emily B et al. (2014) From prediction to function using evolutionary genomics: human-specific ecotypes of Lactobacillus reuteri have diverse probiotic functions. Genome Biol Evol 6:1772-89
Hollister, Emily B; Gao, Chunxu; Versalovic, James (2014) Compositional and functional features of the gastrointestinal microbiome and their effects on human health. Gastroenterology 146:1449-58
Hemarajata, P; Spinler, J K; Balderas, M A et al. (2014) Identification of a proton-chloride antiporter (EriC) by Himar1 transposon mutagenesis in Lactobacillus reuteri and its role in histamine production. Antonie Van Leeuwenhoek 105:579-92