FolC2-mediated folate metabolism contributes to suppression of inflammation by probiotic m>Lactobacillus reuteri m>
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- 作者：Carissa M. Thomas ; Delphine M. A. Saulnier ; Jennifer K. Spinler ; Peera Hemarajata ; Chunxu Gao ; Sara E. Jones ; Ashley Grimm ; Miriam A. Balderas ; Matthew D. Burstein ; Christina Morra ; Daniel Roeth ; Markus Kalkum and James Versalovic
- 刊名：MicrobiologyOpen
- 出版年：2016
- 出版时间：October 2016
- 年：2016
- 卷：5
- 期：5
- 页码：802-818
- 全文大小：599K
- ISSN：2045-8827
文摘
Bacterial-derived compounds from the intestinal microbiome modulate host mucosal immunity. Identification and mechanistic studies of these compounds provide insights into host–microbial mutualism. Specific m>Lactobacillus reuteri m> strains suppress production of the proinflammatory cytokine, tumor necrosis factor (TNF), and are protective in a mouse model of colitis. Human-derived m>L. reuteri m> strain ATCC PTA 6475 suppresses intestinal inflammation and produces 5,10-methenyltetrahydrofolic acid polyglutamates. Insertional mutagenesis identified the bifunctional dihydrofolate synthase/folylpolyglutamate synthase type 2 (m>folC2 m>) gene as essential for 5,10-methenyltetrahydrofolic acid polyglutamate biosynthesis, as well as for suppression of TNF production by activated human monocytes, and for the anti-inflammatory effect of m>L. reuteri m> 6475 in a trinitrobenzene sulfonic acid-induced mouse model of acute colitis. In contrast, m>folC m> encodes the enzyme responsible for folate polyglutamylation but does not impact TNF suppression by m>L. reuteri m>. Comparative transcriptomics between wild-type and mutant m>L. reuteri m> strains revealed additional genes involved in immunomodulation, including previously identified m>hdc m> genes involved in histidine to histamine conversion. The m>folC2 m> mutant yielded diminished m>hdc m> gene cluster expression and diminished histamine production, suggesting a link between folate and histadine/histamine metabolism. The identification of genes and gene networks regulating production of bacterial-derived immunoregulatory molecules may lead to improved anti-inflammatory strategies for digestive diseases.