Research ArticleMICROBIOLOGY

Vancomycin relieves mycophenolate mofetil–induced gastrointestinal toxicity by eliminating gut bacterial β-glucuronidase activity

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Science Advances  07 Aug 2019:
Vol. 5, no. 8, eaax2358
DOI: 10.1126/sciadv.aax2358
  • Fig. 1 Effect of vancomycin on mouse body weight and colonic inflammation.

    (A) Vancomycin was sufficient to reverse MMF-induced weight loss even in the continued presence of MMF. Data represent two separate experiments with four to nine animals for each group and are expressed as means and SD for each time point. (B) Vancomycin induced significant changes (*P < 0.1) in multiple colonic cytokines and chemokines. Each column represents an individual animal.

  • Fig. 2 Vancomycin-induced changes in the gut microbiome.

    Amplicon sequencing of DNA extracted from mouse fecal pellets was used to determine bacterial composition. (A) Stacked bar plots showing relative abundance of bacterial classes in the presence of MMF with and without vancomycin. Vancomycin decreased overall diversity with a gradual predominance of Bacilli. (B) Bacteroides spp. were abundant in the presence of MMF but were rapidly eliminated by the introduction of vancomycin on day 8.

  • Fig. 3 MMF–up-regulated GUS expression and activity are prevented by vancomycin.

    PICRUSt and an enzyme activity assay were used to assess gene expression and GUS activity in mouse fecal pellets. (A) The proportional abundance of KEGG ortholog K01195 increased significantly (*P = 0.006) in the presence of MMF after 4 days. (B) GUS activity in fecal pellets collected from mice consuming MMF also increased significantly (P = 0.03) after 4 days. (C) The introduction of vancomycin on day 8 rapidly eliminated the expression of K01195. (D) Vancomycin, introduced after day 8, abolished GUS activity in fecal pellets (*P < 0.01). All data are plotted as means and SDs with data points for individual samples represented.

  • Fig. 4 Intestinal GUS activity is decreased by vancomycin.

    Mice were treated with MMF or MMF and vancomycin for 8 days, and then GUS activity was imaged using the fluorescent substrate FDGlcU. (A) Ex vivo imaging of the GI tract from control mice. (B) Ex vivo imaging of the mouse GI tract after animals consumed MMF for 8 days. (C) Ex vivo imaging of the GI tract of mice exposed to MMF and vancomycin for 8 days. (D) Quantification of GUS activity in the cecum did not demonstrate a significant increase after 4 or 8 days of MMF exposure, but activity decreased significantly after 4 and 8 days of vancomycin treatment. (E) Quantification of GUS activity in the proximal colon did not demonstrate a significant increase with MMF, but activity decreased significantly after 8 days of vancomycin treatment compared with animals receiving MMF only. *P < 0.05.

  • Fig. 5 Changes in MMF metabolites.

    The concentrations of MMF metabolites were measured in mouse fecal pellets and serum. (A to C) Comparison of MPA, MPAG, and GA levels in mice exposed to MMF only for up to 16 days and mice initially exposed to MMF only for 8 days and then with the addition of vancomycin for 8 days. Vancomycin treatment resulted in significant increases in MPAG and significant decreases in MPA levels (P < 0.05). (D to F) In serum from mice consuming MMF, levels of MPA, MPAG, and GA were not affected after 8 days of treatment with vancomycin. AcMPAG was not detected in the serum. Data are means ± SEM. The mean concentration of each metabolite before (days 0 to 8) and after (days 10 to 16) the introduction of vancomycin was compared independently in each treatment group using a two-way analysis of variance (ANOVA), with *P < 0.0005.

  • Fig. 6 GUS activity in human stool.

    Samples were collected from 11 adult and pediatric heart transplant recipients and 2 healthy, nontransplant controls. The highest level of GUS activity seen in patient 1 correlated with lymphopenia requiring a dose reduction in her MMF. Patient 3 had developed hematochezia and colonic lymphonodular hyperplasia while taking MMF. Patients 10 and 11 had been taken off MMF before sample collection.

Supplementary Materials

  • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/5/8/eaax2358/DC1

    Fig. S1. MMF metabolism.

    Fig. S2. Effect of individual antibiotics (ampicillin, neomycin, metronidazole, or vancomycin) on mouse body weight in the presence of MMF.

    Fig. S3. Tissue weights.

    Fig. S4. Effect of 8 days of exposure to MMF alone or MMF with vancomycin on individual cytokines and chemokines.

    Fig. S5. Changes in bacterial diversity.

    Fig. S6. Changes in bacterial abundance.

    Fig. S7. Intrarectal metabolite effects.

  • Supplementary Materials

    This PDF file includes:

    • Fig. S1. MMF metabolism.
    • Fig. S2. Effect of individual antibiotics (ampicillin, neomycin, metronidazole, or vancomycin) on mouse body weight in the presence of MMF.
    • Fig. S3. Tissue weights.
    • Fig. S4. Effect of 8 days of exposure to MMF alone or MMF with vancomycin on individual cytokines and chemokines.
    • Fig. S5. Changes in bacterial diversity.
    • Fig. S6. Changes in bacterial abundance.
    • Fig. S7. Intrarectal metabolite effects.

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