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Metabolic crosstalk regulates Porphyromonas gingivalis colonization and virulence during oral polymicrobial infection


Many human infections are polymicrobial in origin, and interactions among community inhabitants shape colonization patterns and pathogenic potential1. Periodontitis, which is the sixth most prevalent infectious disease worldwide2, ensues from the action of dysbiotic polymicrobial communities3. The keystone pathogen Porphyromonas gingivalis and the accessory pathogen Streptococcus gordonii interact to form communities in vitro and exhibit increased fitness in vivo3,4. The mechanistic basis of this polymicrobial synergy, however, has not been fully elucidated. Here we show that streptococcal 4-aminobenzoate/para-amino benzoic acid (pABA) is required for maximal accumulation of P. gingivalis in dual-species communities. Metabolomic and proteomic data showed that exogenous pABA is used for folate biosynthesis, and leads to decreased stress and elevated expression of fimbrial adhesins. Moreover, pABA increased the colonization and survival of P. gingivalis in a murine oral infection model. However, pABA also caused a reduction in virulence in vivo and suppressed extracellular polysaccharide production by P. gingivalis. Collectively, these data reveal a multidimensional aspect to P. gingivalisS. gordonii interactions and establish pABA as a critical cue produced by a partner species that enhances the fitness of P. gingivalis while diminishing its virulence.

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Fig. 1: Exogenous pABA enhances P. gingivalis community formation with S. gordonii.
Fig. 2: pABA increases expression of P. gingivalis effectors of community development.
Fig. 3: Trans-omics of the effect of pABA on the tetrahydrofolate metabolic pathway in P. gingivalis.
Fig. 4: Effects of pABA on P. gingivalis in vivo and expression of extracellular polysaccharide.

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Supported by AMED-CREST, AMED, MEXT/JSPS KAKENHI grant numbers 15H05057, and 15K20642 (M.K.), NIH grants DE012505 and DE011111 (R.J.L.), DE023193 (M.W.) DP1 OD009572 (E.M.M.) and DE014372 (M.H.), Army Research Office Grant W911NF-12–1–0390 (E.M.M.), and the Welch Foundation grant F1515 (E.M.M.).

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Authors and Affiliations



M.K., S.A.A. and A.S. performed metabolomics and community experiments. J.R.H., E.L.H., T.W. and D.A.C.B. performed proteomics experiments. Q.W. and D.P.M. performed PCR, blots, ELISAs, protease and attachment assays. Q.W., J.A.H. and H.W. performed animal experiments. M.K., M.W., A.A., H.W., E.M.M., M.H. and R.J.L. designed the study and interpreted data. M.K., M.W., A.A., M.H. and R.J.L. wrote the manuscript.

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Correspondence to Richard J. Lamont.

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The authors declare no competing financial interests.

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Supplementary Information

Supplementary Figures 1–10, Supplementary Tables 1 and 2, Supplementary Table 6

Supplementary Table 1

MS/MS identification of P. gingivalis proteins differentially regulated by pABA

Supplementary Table 3

Metabolomic profiles in P. gingivalis treated with pABA

Supplementary Table 4

Metabolites decreased by pABA-mediated suppression of PLP-dependent enzymes in P. gingivalis

Supplementary Table 5

Metabolite classification pathways

Supplementary Table 7

Raw protein spectral counts

Supplementary Table 8

Raw peptide spectral counts

Supplementary Table 9

Spectral counts of P. gingivalis treated with or without pABA normalized such that their averages are identical for identical biological replicates

Supplementary Table 10

Outlier analysis of proteomic data

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Kuboniwa, M., Houser, J.R., Hendrickson, E.L. et al. Metabolic crosstalk regulates Porphyromonas gingivalis colonization and virulence during oral polymicrobial infection. Nat Microbiol 2, 1493–1499 (2017).

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