Two-carbon folate cycle of commensal Lactobacillus reuteri 6475 gives rise to immunomodulatory ethionine, a source for histone ethylation

• Published in: The FASEB journal Vol. 33; no. 3; p. 3536
• Main Authors: Röth, Daniel, Chiang, Abby J, Hu, Weidong, Gugiu, Gabriel B, Morra, Christina N, Versalovic, James, Kalkum, Markus
• Format: Journal Article
• Language: English
• Published: United States 01.03.2019
• Subjects: Amino Acids - metabolism; Carbon - metabolism; Cell Proliferation - physiology; Cells, Cultured; Culture Media - metabolism; Ethionine - metabolism; Folic Acid - metabolism; Histones - metabolism; Homocysteine - metabolism; Humans; Immunomodulation - physiology; Lactobacillus reuteri - metabolism; Methionine - metabolism; Methylation; Microbiota - physiology; Probiotics - metabolism; THP-1 Cells - metabolism; Tumor Necrosis Factor-alpha - metabolism; lysine ethylation; microbiome; probiotic bacteria; posttranslational modification; ethenyltetrahydrofolate
• ISSN: 1530-6860
• DOI: 10.1096/fj.201801848R

Colonization of the gut by certain probiotic Lactobacillus reuteri strains has been associated with reduced risk of inflammatory diseases and colorectal cancer. Previous studies pointed to a functional link between immunomodulation, histamine production, and folate metabolism, the central 1-carbon pathway for the transfer of methyl groups. Using mass spectrometry and NMR spectroscopy, we analyzed folate metabolites of L. reuteri strain 6475 and discovered that the bacterium produces a 2-carbon-transporting folate in the form of 5,10-ethenyl-tetrahydrofolyl polyglutamate. Isotopic labeling permitted us to trace the source of the 2-carbon unit back to acetate of the culture medium. We show that the 2C folate cycle of L. reuteri is capable of transferring 2 carbon atoms to homocysteine to generate the unconventional amino acid ethionine, a known immunomodulator. When we treated monocytic THP-1 cells with ethionine, their transcription of TNF-α was inhibited and cell proliferation reduced. Mass spectrometry of THP-1 histones revealed incorporation of ethionine instead of methionine into proteins, a reduction of histone-methylation, and ethylation of histone lysine residues. Our findings suggest that the microbiome can expose the host to ethionine through a novel 2-carbon transporting variant of the folate cycle and modify human chromatin via ethylation.-Röth, D., Chiang, A. J., Hu, W., Gugiu, G. B., Morra, C. N., Versalovic, J., Kalkum, M. The two-carbon folate cycle of commensal Lactobacillus reuteri 6475 gives rise to immunomodulatory ethionine, a source for histone ethylation.