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Gut bacterial phospholipase Ds support disease-associated metabolism by generating choline

Nature Microbiology volume 4, pages 155–163 (2019)Cite this article

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Abstract

The essential nutrient choline is metabolized by gut bacteria to the disease-associated metabolite trimethylamine (TMA). However, most of the choline obtained via the diet and present in the human body is incorporated into larger metabolites, including the lipid phosphatidylcholine (PC). Here, we report that many choline-utilizing gut microorganisms can hydrolyse PC using a phospholipase D (PLD) enzyme and further convert the released choline to TMA. Genetic and in vitro characterization of the PLD from Escherichia coli MS 200-1 showed this enzyme is essential for bacterial hydrolysis of PC and prefers this substrate. PLDs are also found in gut bacterial isolates that are unable to convert choline to TMA, suggesting that additional members of the gut microbiota may influence access to this substrate. Unexpectedly, this PLD is only distantly related to characterized PLDs from pathogenic bacteria, suggesting a distinct evolutionary history. Together, these results reveal a previously underappreciated role for gut microorganisms in phospholipid metabolism and a potential target for inhibiting TMA production.

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Fig. 1: The mechanisms by which gut bacteria access choline from choline-containing precursors are poorly defined.
Fig. 2: Choline-utilizing (cut+) gut bacteria can access free choline from PC through the action of a PLD enzyme.
Fig. 3: The E. coli MS 200-1 PLD prefers PC as a substrate.
Fig. 4: Phylogenetic analysis of PLDs.
Fig. 5: PLD-encoding bacteria lacking the cut gene cluster can support choline metabolism by other microorganisms.

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Data availability

The data that support the findings of this study are available from the corresponding author upon request.

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Acknowledgements

The authors thank L. Rajakovich, B. Schneider, S. Irwin, N. Braffman and M. McCallum for helpful discussions and comments on the manuscript. The authors also thank K. Romano and F. Rey for helpful discussions, the provision of strains, and experimental design suggestions. The authors acknowledge financial support from the National Science Foundation (IDBR TYPE A DBI-1832846, EAGER MCB-1650086), the Camille Dreyfus Teacher-Scholar Award (TC-15-003), a Packard Fellowship for Science and Engineering (2013-39267), and a Blavatnik Biomedical Accelerator grant.

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  1. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA

    Carina L. Chittim, Ana Martínez del Campo & Emily P. Balskus

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Contributions

C.L.C. and E.P.B. conceived the study. C.L.C and A.M.d.C. conceived and performed genetic manipulation experiments and analysed the data. C.L.C conceived and performed all biochemical, bioinformatic, and co-culturing experiments and analysed the data. C.L.C. and E.P.B. wrote the manuscript. C.L.C., A.M.d.C. and E.P.B. edited the manuscript.

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Correspondence to Emily P. Balskus.

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Chittim, C.L., Martínez del Campo, A. & Balskus, E.P. Gut bacterial phospholipase Ds support disease-associated metabolism by generating choline. Nat Microbiol 4, 155–163 (2019). https://doi.org/10.1038/s41564-018-0294-4

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