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

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.

• Authors: 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
• Journal: The American journal of pathology (Am J Pathol) Vol. 187 Issue 10 Pg. 2323-2336 (Oct 2017) ISSN: 1525-2191 [Electronic] United States
• PMID: 28917668 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Cytokines
• RNA, Messenger
• Receptors, Histamine H2
• Histamine
• Histidine Decarboxylase

Topics

• Animals
• Carcinogenesis (genetics, pathology)
• Colorectal Neoplasms (blood, diagnostic imaging, genetics, pathology)
• Cytokines (blood)
• Gastrointestinal Microbiome
• Gene Expression Regulation, Neoplastic
• Histamine (biosynthesis)
• Histidine Decarboxylase (genetics, metabolism)
• Humans
• Inflammation (blood, genetics, pathology)
• Intestinal Mucosa (pathology)
• Limosilactobacillus reuteri (metabolism)
• Mice, Inbred BALB C
• Models, Biological
• Myeloid Cells (metabolism)
• Positron-Emission Tomography
• RNA, Messenger (genetics, metabolism)
• Receptors, Histamine H2 (genetics, metabolism)
• Spleen (pathology)
• Survival Analysis