Gut Microbe–Mediated Suppression of Inflammation-Associated Colon Carcinogenesis by Luminal Histamine Production

Chunxu Gao, Bhanu Priya Ganesh, Zhongcheng Shi, Rajesh Rasik Shah, Robert Fultz, Angela Major, Susan Venable, Monica Lugo, Kathleen Hoch, Xiaowei Chen, Anthony Haag, Timothy C. Wang, James Versalovic

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Microbiome-mediated suppression of carcinogenesis may open new avenues for identification of therapeutic targets and prevention strategies in oncology. Histidine decarboxylase (HDC) deficiency has been shown to promote inflammation-associated colorectal cancer by accumulation of CD11b+Gr-1+ immature myeloid cells, indicating a potential antitumorigenic effect of histamine. Here, we demonstrate that administration of hdc+ Lactobacillus reuteri in the gut resulted in luminal hdc gene expression and histamine production in the intestines of Hdc−/− mice. This histamine-producing probiotic decreased the number and size of colon tumors and colonic uptake of [18F]-fluorodeoxyglucose by positron emission tomography in Hdc−/− mice. Administration of L. reuteri suppressed keratinocyte chemoattractant (KC), Il22, Il6, Tnf, and IL1α gene expression in the colonic mucosa and reduced the amounts of proinflammatory, cancer-associated cytokines, keratinocyte chemoattractant, IL-22, and IL-6, in plasma. Histamine-generating L. reuteri also decreased the relative numbers of splenic CD11b+Gr-1+ immature myeloid cells. Furthermore, an isogenic HDC-deficient L. reuteri mutant that was unable to generate histamine did not suppress carcinogenesis, indicating a significant role of the cometabolite, histamine, in suppression of chronic intestinal inflammation and colorectal tumorigenesis. These findings link luminal conversion of amino acids to biogenic amines by gut microbes and probiotic-mediated suppression of colorectal neoplasia.

Original languageEnglish (US)
Pages (from-to)2323-2336
Number of pages14
JournalAmerican Journal of Pathology
Volume187
Issue number10
DOIs
StatePublished - Oct 2017

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Gao, C., Ganesh, B. P., Shi, Z., Shah, R. R., Fultz, R., Major, A., Venable, S., Lugo, M., Hoch, K., Chen, X., Haag, A., Wang, T. C., & Versalovic, J. (2017). Gut Microbe–Mediated Suppression of Inflammation-Associated Colon Carcinogenesis by Luminal Histamine Production. American Journal of Pathology, 187(10), 2323-2336. https://doi.org/10.1016/j.ajpath.2017.06.011