Research ArticleMICROBIOTA

Vitamin B12 modulates the transcriptome of the skin microbiota in acne pathogenesis

See allHide authors and affiliations

Science Translational Medicine  24 Jun 2015:
Vol. 7, Issue 293, pp. 293ra103
DOI: 10.1126/scitranslmed.aab2009
  • Fig. 1. The gene expression profiles of P. acnes in the skin microbiota were distinct between acne patients and healthy individuals.

    (A) On the basis of the gene expression of P. acnes in the skin microbiota, acne patients (labeled in red, “Acne”) formed a separate cluster from healthy individuals (labeled in green, “Healthy”) in an unsupervised hierarchical clustering analysis. (B) One hundred thirty-six differentially expressed P. acnes OGUs were identified between acne patients and healthy individuals. Among them, 109 OGUs were up-regulated and 27 OGUs were down-regulated in acne patients. The OGU names are listed in table S2.

  • Fig. 2. A schematic of the metabolic pathways in P. acnes illustrating the observed differentially expressed OGUs in acne patients compared to healthy individuals.

    Genes encoding sugar transport and sugar metabolism pathways were up-regulated in acne patients. Genes in the vitamin B12 biosynthesis and fatty acid biosynthesis pathways were down-regulated. FC, fold change. The full gene names are listed in table S3.

  • Fig. 3. Vitamin B12 biosynthesis genes were down-regulated in the skin microbiota of acne patients compared to healthy individuals.

    Down-regulation of the genes in P. acnes vitamin B12 biosynthesis pathway was validated in a separate cohort of acne patients (n = 9) and healthy individuals (n = 15). Consistent with the RNA-Seq data, cysG+cbiX and cbiL were significantly down-regulated, and btuR showed a lower average expression level in acne patients compared to healthy individuals. Significance was determined by Student’s t test. The mean expression level of each gene is indicated by a black bar. The gene expression data are listed in table S4.

  • Fig. 4. Vitamin B12 supplementation in healthy subjects repressed P. acnes cob/cbi operons.

    The gene expression levels of cbiL, cysG+cbiX, and btuR in P. acnes vitamin B12 biosynthesis pathway were significantly repressed in the healthy subjects (n = 10) on day 14 after vitamin B12 supplementation, to a level similar to those observed in the acne patients (n = 9). Without vitamin B12 supplementation, the expression levels of these genes did not change significantly on day 2 and day 14 compared to day 0 (n = 9). The expression levels, quantified by qRT-PCR, for each gene on day 0, day 2, and day 14 are shown. Data from healthy subjects with vitamin B12 supplementation are shown in purple, and data from those without supplementation are shown in green. As a comparison, data from the acne patients are shown in red. The mean expression level of each gene is indicated by a black bar. Significance was determined by Student’s t test. The gene expression data are listed in tables S5A and S5B.

  • Fig. 5. Vitamin B12 supplementation in the host altered the transcriptome of P. acnes in the skin microbiota.

    (A) The differentially expressed P. acnes OGUs between day 0 and day 14 samples from the healthy subjects supplemented with vitamin B12. The red and green colors represent the fold change of the OGUs. Red indicates up-regulation after vitamin B12 supplementation and green indicates down-regulation. The functional categories of the OGUs are labeled by the colored bars next to the OGU names. (B) The P. acnes gene expression profile of subject HL414 on day 14 after vitamin B12 supplementation (HL414_Day14) was similar to those from the acne patients and clustered together. The day 0 sample from subject HL414 (“HL414_Day0”, healthy skin, before vitamin B12 supplementation) was similar to the samples from other healthy subjects. Samples from the acne patients were labeled in red (“Acne”), and samples from the healthy subjects were labeled in green (“Healthy,” “Day0,” “Day14”), except for HL414_Day14.

  • Fig. 6. Vitamin B12 supplementation repressed the expression of cob/cbi operons in the vitamin B12 biosynthesis pathway and promoted porphyrin production in P. acnes cultures.

    (A) The expression levels of cbiL, cysG+cbiX, and btuR were significantly repressed on day 2, day 8, and day 14 after vitamin B12 supplementation in P. acnes cultures. The experiments were repeated three times independently. Each dot represents the average gene expression level of two to three technical replicates in each independent experiment. The dotted lines indicate the changes between the P. acnes cultures in medium alone (black) and the cultures in medium with vitamin B12 supplementation (red). The mean of the gene expression levels from the three independent experiments is shown as a black bar. Significance was determined by Student’s t test. The gene expression data are listed in table S7. (B) Porphyrin production in P. acnes cultures on day 8 and day 14 after vitamin B12 supplementation was significantly increased. Significance was determined by Student’s t test. Data are presented as means ± SD. The experiments were repeated three times independently with three to four biological replicates each time. The porphyrin levels are listed in table S8.

  • Fig. 7. A model of vitamin B12 modulating the transcriptional and metabolic activities of the skin bacterium P. acnes in acne pathogenesis.

    In healthy skin, when the host vitamin B12 level is normal, the vitamin B12 biosynthesis pathway in P. acnes is expressed and porphyrins are produced at a low level. When the host vitamin B12 level is elevated, it signals transcriptional changes in P. acnes. The levels of 2-oxoglutarate and l-glutamate are increased, and the vitamin B12 biosynthesis in P. acnes is repressed. The metabolic flow of l-glutamate is shunted toward the porphyrin biosynthesis pathway, leading to an overproduction of porphyrins by P. acnes in the follicle. The overproduced porphyrins, secreted by P. acnes, induce an inflammatory response in the host cells, leading to acne development in a subset of individuals. 2-OG, 2-oxoglutarate; l-Glu, l-glutamate.

Supplementary Materials

  • www.sciencetranslationalmedicine.org/cgi/content/full/7/293/293ra103/DC1

    Materials and Methods

    Fig. S1. The metatranscriptome composition of the skin microbiota in follicles.

    Fig. S2. The KEGG pathways expressed in all the samples.

    Fig. S3. The KEGG pathways with differentially expressed P. acnes OGUs.

    Fig. S4. The cob/cbi operons in P. acnes.

    Fig. S5. Differentially expressed P. acnes OGUs in sample HL414_Day14 compared to the other day 14 samples.

    Fig. S6. The biosynthesis of porphyrins is inversely correlated with the biosynthesis of vitamin B12 in P. acnes.

    Fig. S7. A comparison of the samples collected from opposite sides of the nose of the same individual using the Bioré strip method and the tape stripping method.

    Fig. S8. Rarefaction curves indicate sufficient sequencing depths of the samples.

    Table S1. High sequencing depths of the metatranscriptomic data.

    Table S2. Differentially expressed OGUs shown in Fig. 1B.

    Table S3. Full names of the genes and substrates shown in Fig. 2.

    Table S4. The relative expression levels (log10) of the vitamin B12 biosynthesis genes in the skin microbiota of the healthy individuals and acne patients shown in Fig. 3.

    Table S5A. The relative expression levels (log10) of the vitamin B12 biosynthesis genes in the skin microbiota of the healthy subjects shown in Fig. 4.

    Table S5B. The relative expression levels (log10) of the vitamin B12 biosynthesis genes in the skin microbiota of the acne patients shown in Fig. 4.

    Table S6. The differentially expressed OGUs in both the comparison between sample HL414_Day14 and other day 14 samples and the comparison between day 0 and day 14 samples in the vitamin B12 supplementation study.

    Table S7. The relative expression levels (log10) of the vitamin B12 biosynthesis genes in the P. acnes cultures shown in Fig. 6A.

    Table S8. The porphyrin levels detected in the P. acnes cultures shown in Fig. 6B.

    References (7482)

  • Supplementary Material for:

    Vitamin B12 modulates the transcriptome of the skin microbiota in acne pathogenesis

    Dezhi Kang, Baochen Shi, Marie C. Erfe, Noah Craft, Huiying Li*

    *Corresponding author. E-mail: huiying{at}mednet.ucla.edu

    Published 24 June 2015, Sci. Transl. Med. 7, 293ra103 (2015)
    DOI: 10.1126/scitranslmed.aab2009

    This PDF file includes:

    • Materials and Methods
    • Fig. S1. The metatranscriptome composition of the skin microbiota in follicles.
    • Fig. S2. The KEGG pathways expressed in all the samples.
    • Fig. S3. The KEGG pathways with differentially expressed P. acnes OGUs.
    • Fig. S4. The cob/cbi operons in P. acnes.
    • Fig. S5. Differentially expressed P. acnes OGUs in sample HL414_Day14 compared to the other day 14 samples.
    • Fig. S6. The biosynthesis of porphyrins is inversely correlated with the biosynthesis of vitamin B12 in P. acnes.
    • Fig. S7. A comparison of the samples collected from opposite sides of the nose of the same individual using the Bioré strip method and the tape stripping method.
    • Fig. S8. Rarefaction curves indicate sufficient sequencing depths of the samples.
    • Table S1. High sequencing depths of the metatranscriptomic data.
    • Table S2. Differentially expressed OGUs shown in Fig. 1B.
    • Table S3. Full names of the genes and substrates shown in Fig. 2.
    • Table S4. The relative expression levels (log10) of the vitamin B12 biosynthesis genes in the skin microbiota of the healthy individuals and acne patients shown in
      Fig. 3.
    • Table S5A. The relative expression levels (log10) of the vitamin B12 biosynthesis genes in the skin microbiota of the healthy subjects shown in Fig. 4.
    • Table S5B. The relative expression levels (log10) of the vitamin B12 biosynthesis genes in the skin microbiota of the acne patients shown in Fig. 4.
    • Table S6. The differentially expressed OGUs in both the comparison between sample HL414_Day14 and other day 14 samples and the comparison between day
      0 and day 14 samples in the vitamin B12 supplementation study.
    • Table S7. The relative expression levels (log10) of the vitamin B12 biosynthesis genes in the P. acnes cultures shown in Fig. 6A.
    • Table S8. The porphyrin levels detected in the P. acnes cultures shown in Fig. 6B.
    • References (7482)

    [Download PDF]

Navigate This Article