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.
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.
|Röth, Daniel; Chiang, Abby J; Hu, Weidong et al. (2018) Two-carbon folate cycle of commensal Lactobacillus reuteri 6475 gives rise to immunomodulatory ethionine, a source for histone ethylation. FASEB J :fj201801848R|
|Ganesh, B P; Hall, A; Ayyaswamy, S et al. (2018) Diacylglycerol kinase synthesized by commensal Lactobacillus reuteri diminishes protein kinase C phosphorylation and histamine-mediated signaling in the mammalian intestinal epithelium. Mucosal Immunol 11:380-393|
|Ganesh, Bhanu Priya; Fultz, Robert; Ayyaswamy, Sriram et al. (2018) Microbial interactions with the intestinal epithelium and beyond: Focusing on immune cell maturation and homeostasis. Curr Pathobiol Rep 6:47-54|
|Ihekweazu, Faith D; Versalovic, James (2018) Development of the Pediatric Gut Microbiome: Impact on Health and Disease. Am J Med Sci 356:413-423|
|Gao, Chunxu; Ganesh, Bhanu Priya; Shi, Zhongcheng et al. (2017) Gut Microbe-Mediated Suppression of Inflammation-Associated Colon Carcinogenesis by Luminal Histamine Production. Am J Pathol 187:2323-2336|
|Engevik, Melinda A; Versalovic, James (2017) Biochemical Features of Beneficial Microbes: Foundations for Therapeutic Microbiology. Microbiol Spectr 5:|
|Pokusaeva, K; Johnson, C; Luk, B et al. (2017) GABA-producing Bifidobacterium dentium modulates visceral sensitivity in the intestine. Neurogastroenterol Motil 29:|
|Davidovics, Zev H; Carter, Beth A; Luna, Ruth Ann et al. (2016) The Fecal Microbiome in Pediatric Patients With Short Bowel Syndrome. JPEN J Parenter Enteral Nutr 40:1106-1113|
|Chehoud, Christel; Dryga, Anatoly; Hwang, Young et al. (2016) Transfer of Viral Communities between Human Individuals during Fecal Microbiota Transplantation. MBio 7:e00322|
|Thomas, Carissa M; Saulnier, Delphine M A; Spinler, Jennifer K et al. (2016) FolC2-mediated folate metabolism contributes to suppression of inflammation by probiotic Lactobacillus reuteri. Microbiologyopen 5:802-818|
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