Gut L-Histidine Metabolism and Histamine Signaling in Colonic Neoplasia

Summary

Principal Investigator: James Versalovic
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2013-08-01 - 2018-07-31
more information: NIH RePORT

Top Publications

  1. pmc Compositional and functional features of the gastrointestinal microbiome and their effects on human health
    Emily B Hollister
    Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas Department of Pathology, Texas Children s Hospital, Houston, Texas
    Gastroenterology 146:1449-58. 2014

Research Grants

  1. Dietary Rice Bran Phytochemicals and Microbial Metabolites for Colon Chemoprevent
    Tiffany L Weir; Fiscal Year: 2013
  2. INTESTINAL IMMUNE SYSTEM IN HOST-ENVIRONMENT INTERACTION
    MARTIN FREDERICK KAGNOFF; Fiscal Year: 2013
  3. Role of Eicosanoids in Renal Function
    NANCY JOAN BROWN; Fiscal Year: 2013
  4. Primary Immune Deficiency Treatment Consortium
    Morton Cowan; Fiscal Year: 2013
  5. Biology &Transplantation of the Human Stem Cell
    John E Wagner; Fiscal Year: 2013
  6. Autophagy genes and the microbiome in Crohn's Disease
    Ramnik J Xavier; Fiscal Year: 2013
  7. BARRIER FUNCTION OF THE GI TRACT IN HEALTH AND DISEASE
    W Allan Walker; Fiscal Year: 2013
  8. University of Maryland Greenebaum Cancer Center Support Grant
    Kevin J Cullen; Fiscal Year: 2013
  9. INNATE AND ADAPTIVE IMMUNITY IN IBD
    Charles O Elson; Fiscal Year: 2013
  10. SPORE IN GASTROINTESTINAL CANCER
    Scott E Kern; Fiscal Year: 2013

Detail Information

Publications1

  1. pmc Compositional and functional features of the gastrointestinal microbiome and their effects on human health
    Emily B Hollister
    Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas Department of Pathology, Texas Children s Hospital, Houston, Texas
    Gastroenterology 146:1449-58. 2014
    ..Core features of the healthy microbiome might be defined and targeted to prevent disease and optimize human health...

Research Grants30

  1. Dietary Rice Bran Phytochemicals and Microbial Metabolites for Colon Chemoprevent
    Tiffany L Weir; Fiscal Year: 2013
    ..These findings will serve as critical, pilot data on rice bran-mediated changes in microbial metabolism for a definitive, mechanism based chemopreventive rice bran-microbe- metabolite investigation using a R01 mechanism. ..
  2. INTESTINAL IMMUNE SYSTEM IN HOST-ENVIRONMENT INTERACTION
    MARTIN FREDERICK KAGNOFF; Fiscal Year: 2013
    ..The research projects are supported by four Cores: a Mouse Model Core, a Histopathology Core, an Imaging and Cell Sorting Core and an Administrative Core. ..
  3. Role of Eicosanoids in Renal Function
    NANCY JOAN BROWN; Fiscal Year: 2013
    ..These are needed for the development of meaningful approaches for: a) the unequivocal definition of human pathophysiological significance, and b) future pharmacological targeting, and clinical diagnosis and intervention. ..
  4. Primary Immune Deficiency Treatment Consortium
    Morton Cowan; Fiscal Year: 2013
    ..These studies will resolve critical questions concerning HCT for these disorders and form the basis for future prospective clinical trials. ..
  5. Biology &Transplantation of the Human Stem Cell
    John E Wagner; Fiscal Year: 2013
    ..abstract_text> ..
  6. Autophagy genes and the microbiome in Crohn's Disease
    Ramnik J Xavier; Fiscal Year: 2013
    ..The results anticipated from these studies will advance our understanding of CD by determining how the interactions and influences of host genetics, the microbiome and the immune response contribute to Crohn's disease. ..
  7. BARRIER FUNCTION OF THE GI TRACT IN HEALTH AND DISEASE
    W Allan Walker; Fiscal Year: 2013
    ..abstract_text> ..
  8. University of Maryland Greenebaum Cancer Center Support Grant
    Kevin J Cullen; Fiscal Year: 2013
    ..Reflecting our remarkable and continued growth, UMGCC seeks to renew its CCSG to enhance and expand its efforts in high-quality and clinically relevant cancer research. ..
  9. INNATE AND ADAPTIVE IMMUNITY IN IBD
    Charles O Elson; Fiscal Year: 2013
    ..The long-term goal is to increase our understanding of the fundamental mechanisms of IBD in order to develop better diagnostic and therapeutic strategies for patients...
  10. SPORE IN GASTROINTESTINAL CANCER
    Scott E Kern; Fiscal Year: 2013
    ..Alison Klein. The Career Development Program (Dr. Scott Kern) aids the emergence of new investigators and the Research Developmental Program (Dr. Bert Vogelstein) provides rapid funding of innovative directions. ..
  11. Tissue compartmentalization of human lymphocytes
    Donna L Farber; Fiscal Year: 2013
    ..The results obtained will lead to new strategies for tissue targeting of T cell responses in vaccines and immunotherapies. ..
  12. Silvio O. Conte Digestive Diseases Research Core Centers
    Michael H Nathanson; Fiscal Year: 2013
    ..A Pilot Feasibility Program supports 1-2 year small grants for new scientific initiatives. The Enrichment Program consists of research seminars, symposia, and retreats. ..
  13. Microbial Induction of Colon Cancer and Mechanisms (PQ12)
    CYNTHIA SEARS; Fiscal Year: 2013
    ....
  14. CENTER FOR THE STUDY OF INFLAMMATORY BOWEL DISEASE
    Ramnik J Xavier; Fiscal Year: 2013
    ..These goals are fostered by Pilot/Feasibility Study awards which support new research initiatives as well as an enrichment program of seminars, workshops and symposia. ..
  15. Regulation of intestinal inflammation and tumorigenesis by Nlrp6
    Grace Y Chen; Fiscal Year: 2013
    ....
  16. Gut microbiota and inflammatory monocytes in colorectal cancer
    Wendy S Garrett; Fiscal Year: 2013
    ..Our proposal examines the role of inflammatory cells and gut bacteria in driving cancer in the colon. ..
  17. Center for Gene Therapy of Cystic Firbosis
    John F Engelhardt; Fiscal Year: 2013
    ..These efforts have led to numerous basic and applied research findings that have enhanced the utility of gene therapies to both study and treat genetic diseases. ..
  18. Molecular Analyses and Interventions for Biodefense and Emerging Pathogens
    Olaf Schneewind; Fiscal Year: 2013
    ..Research and training at the GLRCE is governed by a mechanism involving ongoing review of scientific excellence and translational goals, inter-institutional advisory boards and external scientific advisory bodies. ..
  19. PAHs: New Technologies and Emerging Health Risks
    David E Williams; Fiscal Year: 2013
    ..Accomplishing these goals will provide significant scientific advancement and improve the quality of life for impacted communities. ..
  20. Gut microflora: Impact on neonatal immunity, viral gastroenteritis and vaccines
    ANASTASIA NICKOLAEVNA VLASOVA; Fiscal Year: 2013
    ..Our findings will contribute to alternative low cost probiotic treatments applicable to infants (or mothers) to moderate HRV disease, enhance oral vaccine efficacy, and reduce infant morbidity and mortality. ..
  21. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  22. Gene Networks controlling macrophage-adipocyte interactions in insulin
    Christopher K Glass; Fiscal Year: 2013
    ..abstract_text> ..
  23. Integrative Metabolic Adaptations to Enviromental and Nutritional Challenge
    MORRIS JAY BIRNBAUM; Fiscal Year: 2013
    ..The projects are supported by three Cores that provide histochemical analysis, generation of genetically modified mice, and their metabolic phenotyping. ..
  24. NLR signaling in colitis and colorectal tumorigenesis
    Thirumala Devi Kanneganti; Fiscal Year: 2013
    ....
  25. DRUG ABUSE RESEARCH CENTER
    Solomon H Snyder; Fiscal Year: 2013
    ....
  26. Neurodevelopment and Improving Children's Health following EtS exposure (NICHES)
    Susan Kay Murphy; Fiscal Year: 2013
    ....
  27. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013
    ..Through all of its activities, the Center improves communication, promotes collaboration, develops careers and generally enriches the intellectual climate for digestive disease research. ..