Gut Microbe-Mediated Suppression of Inflammation-Associated Colon Carcinogenesis by Luminal Histamine Production.
Open accessAbstract
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 [18 F]-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.
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Gut l-histidine levels may be decreased in older adults, which could lead to an altered immune state.
“In total, these results indicate that gut l-histidine levels may be decreased in older adults, which could lead to an altered immune state, as l-histidine metabolites have been demonstrated to influence colonic inflammation (Gao et al., 2017).”
From Gut microbiome stability and dynamics in healthy donors and patients with non-gastrointestinal cancers (2021) · cites this paper as Gao et al., 2017
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- Authors
- 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.
- Affiliations
- Baylor College of Medicine (US)
- Texas Children's Hospital (US)
- Columbia University (US)
- Corresponding author
- Versalovic, James
- ORCID
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2017-10
- Volume
- 187
- Issue
- 10
- Pages
- 2323-2336
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC5809336
- OpenAlex
- W2755306162
- Cited by
- 122
- References
- 61
- Citations by year
- 2026: 9 · 2025: 9 · 2024: 15 · 2023: 16 · 2022: 13 · 2021: 20 · 2020: 15 · 2019: 11 · 2018: 11 · 2017: 3
- FWCI
- 8.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- American Journal Of Pathology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes, Digestive and Kidney Diseases (R01 DK065075)
- Texas Medical Center Digestive Disease Center (P30 DK56338)
- National Cancer Institute (U01 CA170930)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Cancer Research and Treatments
- Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Keywords
- histamine, histidine decarboxylase, Lactobacillus reuteri, probiotics, colorectal carcinogenesis, inflammation-associated colorectal cancer, gut microbiota, immature myeloid cells, keratinocyte chemoattractant, IL-22, interleukin-6, TNF-α, IL-1α, biogenic amines, amino acid metabolism, tumor suppression
- MeSH terms
- Gastrointestinal Microbiome, Animals, Histamine, Histidine Decarboxylase, Humans, Inflammation, Intestinal Mucosa, Mice, Inbred BALB C, Models, Biological, Receptors, Histamine H2, RNA, Messenger, Spleen, Colorectal Neoplasms, Gene Expression Regulation, Neoplastic, Survival Analysis, Cytokines, Myeloid Cells, Positron-Emission Tomography, Limosilactobacillus reuteri, Carcinogenesis
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