Inflammatory bowel disease (IBD) is a well-known risk factor for the development of
colorectal cancer. Prior studies have demonstrated that microbial
histamine can ameliorate intestinal
inflammation in mice. We tested the hypothesis whether microbe-derived
luminal histamine suppresses
inflammation-associated
colon cancer in Apcmin/+ mice. Mice were colonized with the human-derived Lactobacillus reuteri. Chronic
inflammation was induced by repeated cycles of low-dose
dextran sulfate sodium (DSS). Mice that were given
histamine-producing L. reuteri via oral gavage developed fewer colonic
tumors, despite the presence of a complex mouse gut microbiome. We further demonstrated that administration of a
histamine H1-receptor (H1R) antagonist suppressed
tumorigenesis, while administration of
histamine H2-receptor (H2R) antagonist significantly increased both
tumor number and size. The bimodal functions of
histamine include protumorigenic effects through H1R and antitumorigenic effects via H2R, and these results were supported by gene expression profiling studies on
tumor specimens of patients with
colorectal cancer. Greater ratios of gene expression of H2R ( HRH2) vs. H1R ( HRH1) were correlated with improved overall survival outcomes in patients with
colorectal cancer. Additionally, activation of H2R suppressed phosphorylation of
mitogen-activated protein kinases (MAPKs) and inhibited
chemokine gene expression induced by H1R activation in
colorectal cancer cells. Moreover, the combination of a H1R antagonist and a H2R agonist yielded potent suppression of
lipopolysaccharide-induced MAPK signaling in macrophages. Given the impact on intestinal epithelial and immune cells, simultaneous modulation of H1R and H2R signaling pathways may be a promising therapeutic target for the prevention and treatment of
inflammation-associated
colorectal cancer. NEW & NOTEWORTHY
Histamine-producing Lactobacillus reuteri can suppress development of
inflammation-associated
colon cancer in an established mouse model. The net effects of
histamine may depend on the relative activity of H1R and H2R signaling pathways in the intestinal mucosa. Our findings suggest that treatment with H1R or H2R antagonists could yield opposite effects. However, by harnessing the ability to block H1R signaling while stimulating H2R signaling, novel strategies for suppression of intestinal
inflammation and colorectal
neoplasia could be developed.