In a study published yesterday in The American Journal of Pathology, researchers describe how administration of histamine-producing gut microbes to mice lacking the enzyme histidine decarboxylase (HDC) reduced inflammation and tumor formation in a mouse model of colorectal cancer (CRC). These results suggest that administration of probiotics to alter the gut microbiome may be an effective new strategy for prevention or treatment of inflammatory bowel disease-associated CRC.
For their study, the researchers orally administered the probiotic Lactobacillus reuteri 6475 or a placebo to mice deficient in HDC, the enzyme required to convert histidine to histamine. Lactobacillus reuteri 6475 possesses the histidine decarboxylase gene (hdc+) and can convert histidine to histamine. Administration of the probiotic occurred either before or after the mice received a single dose of a colonic carcinogen (azoxymethane) plus an inflammation-inducing chemical (DSS) to induce tumor formation. The mice were sacrificed fifteen weeks later and their tissues were removed for study.
It was confirmed that the probiotic increased expression of bacterial HDC and histamine in the mouse colons. Using PET to visualize the tumors revealed the control-treated mice to show evidence of tumors and increased glucose uptake in the colon walls while the mice given a probiotic had fewer and smaller tumors and diminished glucose uptake. Inactive L. reuteri strains had no probiotic effects and did not decrease tumor formation or glucose uptake.
In mice administered the probiotic, gene expression was suppressed for pro-inflammatory cytokines and cytokine concentrations in plasma were decreased. This may indicate that the cancer-suppressing actions of the probiotic work via enhanced maturation of circulating myeloid cells and associated reduction of pro-inflammatory cytokines.
While the role of histamine in human cancer is still unclear, data obtained from 2,113 CRC patient samples revealed better survival with elevated HDC and histamine receptor expression, indicating that HDC generating probiotics may one day be used for clinical treatment.
Image: Figure shows presence of colonic tumors (MRS/AOM+DSS panel) by positron emission tomography imaging. Tumor activity is significantly diminished in the presence of the histamine-producing probiotic (L. reuteri 6475/AOM+DSS). Image courtesy of The American Journal of Pathology.