TY - JOUR
T1 - Two-carbon folate cycle of commensal Lactobacillus reuteri 6475 gives rise to immunomodulatory ethionine, a source for histone ethylation
AU - Röth, Daniel
AU - Chiang, Abby J.
AU - Hu, Weidong
AU - Gugiu, Gabriel B.
AU - Morra, Christina N.
AU - Versalovic, James
AU - Kalkum, Markus
N1 - Funding Information:
D.R., A.J.C., C.N.M., J.V., and M.K were supported by U.S. National Institutes of Health (NIH), National Cancer Institute Grant U01 CA170930 (to J.V.). The use of the City of Hope Mass Spectrometry and Proteomics core facility was partially supported by NIH, National Cancer Institute Grant P30 CA33572. The authors declare no conflicts of interest.
Publisher Copyright:
© FASEB
PY - 2019/3/1
Y1 - 2019/3/1
N2 - 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.—Roth, 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. FASEB J. 33,3536-3548 (2019). www.fasebj.org.
AB - 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.—Roth, 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. FASEB J. 33,3536-3548 (2019). www.fasebj.org.
KW - ethenyltetrahydrofolate
KW - lysine ethylation
KW - microbiome
KW - posttranslational modification
KW - probiotic bacteria
UR - http://www.scopus.com/inward/record.url?scp=85071953736&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85071953736&partnerID=8YFLogxK
U2 - 10.1096/fj.201801848R
DO - 10.1096/fj.201801848R
M3 - Article
C2 - 30452879
AN - SCOPUS:85071953736
SN - 0892-6638
VL - 33
SP - 3536
EP - 3548
JO - FASEB Journal
JF - FASEB Journal
IS - 3
ER -