Lactobacillus reuteri suppresses inflammation-associated colon carcinogenesis in mice by histamine production

Previous research has shown that the human gut microbiota may mediate suppression of carcinogenesis through its interaction with host immunity. Among cancer types, colorectal cancer (CRC) is the third most common cancer and the third leading cause of cancer death in the United States. However, little is known regarding whether manipulating the gut microbiota could help in its prevention and treatment.

A new study, led by Prof. James Versalovic from the Department of Pathology at Texas Children’s Hospital and Baylor College of Medicine in Houston, has found that histamine-producing Lactobacillus reuteri reduces inflammation and suppresses colon tumours in mice.

Previous research in mice has shown that the lack of functional histidine decarboxylase (HDC) -the unique enzyme responsible for histamine generation through the conversion of L-histidine to histamine- promotes inflammation-associated colon and skin carcinogenesis through the accumulation of a particular subset of immune cells that are recruited early on in chemical carcinogenesis, called CD11b+Gr-1+ immature myeloid cells. Hence, histamine is thought to have a potential antitumorigenic effect.

The researchers orally administered the histamine-generating probiotic L. reuteri 6475 (each mouse received 5 x 109 colony-forming units of bacteria in 0.2 mL of culture) to mice lacking the enzyme HDC (Hdc/ mice); control mice received a placebo. The probiotic was administered both before and after the animals received a single dose of azoxymethane -a chemical substance that induces colonic carcinogenesis- together with dextran sulfate sodium (DSS) -an inflammation-inducing chemical- to induce tumour formation. 15 weeks after treatment, mice were sacrificed for tissue recovery.

The probiotic L. reuteri 6475 led to an increased expression of bacterial HDC genes and also increased amounts of histamine in the luminal contents of the mice.

By using positron emission tomography to visualize the tumours, researchers found probiotic-treated mice had fewer and smaller tumours and significantly decreased areas of glucose uptake, whereas control mice showed evidence of tumours and increased glucose uptake in colonocytes. These data show that the probiotic L. reuteri can lead to attenuation of colonic tumorigenesis in mice.

Noticeably, a HDC-deficient L. reuteri mutant -which was unable to generate histamine- did not suppress carcinogenesis; the mice treated with L. reuteri strains deficient in HDC activity showed increased tumour formation and increased abdominal glucose uptake, which indicates the primary role of histamine in suppressing chronic intestinal inflammation and colorectal tumorigenesis in mice.

Histamine-generating L. reuteri acted at three main levels in reducing inflammation induced by the carcinogen plus DSS: 1) Decreasing plasma concentrations of the pro-inflammatory cytokines keratinocyte chemoattractant (KC), interleukin (IL)-6, and IL-22; 2) Suppressing KC, IL-6, IL-22, tumour necrosis factor (TNF-a), and IL-1a gene expression in the colon, and 3) Counteracting an increase in immature myeloid cells induced by the carcinogen in the spleen. On the whole, these results show that the histamine-generating probiotic L. reuteri may attenuate colon carcinogenesis in mice through reducing several pro-inflammatory cytokines and enhancing maturation of circulating myeloid cells in the spleen. These results open a new window for targeting CRC in humans via specific manipulation of the gut microbiome.

According to the journal’s press release: “[Data analysis of] 2,113 CRC patient samples taken from 15 datasets [showed] better survival in patients with elevated patterns of HDC and histamine receptor gene expression. These findings indicate that histamine-generating probiotics, in the presence of sufficient protein (L-histidine) intake, may improve outcomes for patients with sporadic and inflammatory bowel disease-associated CRC”.

In conclusion, these findings suggest that the biogenic amine histamine is involved in the gut microbiota-mediated suppression of inflammation-associated colon carcinogenesis in mice. Further studies are needed in order to clarify the role of luminal conversion of L-histidine from diet to histamine by the gut microbiota as a factor involved in susceptibility to CRC.

 

Reference:

Gao C, Ganesh BP, Shi Z, et al. Gut microbe-mediated suppression of inflammation-associated colon carcinogenesis by luminal histamine production. Am J Pathol. 2017; 187(10):2323-36. doi: 10.1016/j.ajpath.2017.06.011.

Andreu Prados
Andreu Prados
Andreu Prados holds a Bachelor of Science Degree in Pharmacy & Human Nutrition and Dietetics. Science writer specialised in gut microbiota and probiotics, working also as lecturer and consultant in nutrition and healthcare. Follow Andreu on Twitter @andreuprados