Research ArticleHost-Microbe Interactions

Host mitochondria influence gut microbiome diversity: A role for ROS

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Science Signaling  02 Jul 2019:
Vol. 12, Issue 588, eaaw3159
DOI: 10.1126/scisignal.aaw3159

Figures

  • Fig. 1 mtDNA genotypes correlate with gut microbiota composition.

    (A to E) 16S rRNA marker gene sequencing analysis of microbiota in fecal samples from C57BL/6J mice with the indicated mtDNA genotypes. Shannon diversity index (A) data and linear regression fit across groups of at least nine mice per group are from at least three independent breeding pairs per group. Principal coordinates analysis (PCoA) of (B) weighted UniFrac and (C) unweighted UniFrac distance between samples from all experiments. The percent total variation between samples is indicated on each axis, and ellipses represent the 80% confidence interval for samples in each group. The relative abundance of five major bacterial taxa (D) and Bacteroidetes/Firmicutes (B/F) ratio (E) with linear regression fit across all samples. *P < 0.05, **P < 0.01, and ***P < 0.001 by linear mixed-effects models with ordered factors (A), permutational multivariate analysis of variance (PERMANOVA) test (B and C), generalized linear mixed-effects models with ordered factors (D), or linear mixed-effects models on log-transformed ratios with ordered factors (E).

  • Fig. 2 The ND6P25L mtDNA mutation reduces gut microbiota diversity in C57BL/6J mice.

    (A to C) 16S rRNA marker gene sequence analysis of microbiota in fecal samples from mice harboring the mtDNA ND6P25L on the C57BL/6J nuclear background. Shannon diversity index (A) data and medians ± interquartile ranges of 16 mice per group are from at least three independent breeding pairs per group. Data were analyzed using linear mixed-effects models. Principal coordinates analysis of (B) weighted UniFrac distance between samples from all experiments visualizing community amount differences between samples, where percent total variation captured by each axis is indicated. Ellipses represent the 80% confidence interval for samples in each group. The relative abundance of five major bacterial taxa (C) in mice with the indicated mtDNA with medians ± interquartile ranges are from all samples. *P < 0.05 and **P < 0.01 by linear mixed-effects models (A), PERMANOVA test (B), or generalized linear mixed-effects models (C).

  • Fig. 3 Inherited host genotype determines the gut microbiome composition.

    (A) The experimental design for cross-fostering between C57BL/6EiJ (red) and C57BL/6J (purple) mice. During the first 24 hours after birth, the pups were transferred between the mothers of the opposite genotype, the pups were weaned at 3 weeks, and fecal samples were collected from the pups at 2 months of age. (B and C) 16S rRNA marker gene sequence analysis of microbiota in fecal samples from pups that fostered with mothers of different mtDNA genotypes. Shannon diversity index (B) data represent medians ± interquartile ranges of at least 10 mice per group in fostered (middle boxes) and nonfostered (outside boxes) pups from at least three independent breeding pairs per group. The relative abundances of five major bacterial taxa (C) in fostered (middle boxes) and nonfostered (outside boxes) pups with medians ± interquartile ranges are from all samples. (D) Mitochondrial ROS abundance detected by Amplex Red analysis of freshly isolated liver mitochondria from the indicated mice. Data are means ± SD of three mice per group. (E) Microscopy analysis of NADH fluorescence lifetime in cross sections of mouse intestine from the indicated strains. Data are means ± SD of at least five mice per group. *P < 0.05, **P < 0.01, and ***P < 0.001 by linear mixed-effects model (B), generalized linear mixed-effects model (C), or Student’s t test (D and E).

  • Fig. 4 Changes in host mitochondrial ROS abundance reshape the microbiota community.

    (A and B) 16S rRNA marker gene sequencing analysis of microbiota in fecal samples from mice after aging, NAC treatment, or mCAT transgene expression. Shannon diversity index (A) data and the relative abundance of five major bacterial taxa (B) are medians ± interquartile ranges of at least 12 mice per group from at least three independent breeding pairs per group. (C) ROS abundance detected by Amplex Red assay in lysates of liver tissue from NAC treatment of wild-type (WT) C57BL/6J mice or WT and mCAT transgenic mice. Data are means ± SD from three independent experiments. (D) Quantitative reverse transcription polymerase PCR (qRT-PCR) analysis of human mCAT mRNA expression in the liver and small intestine tissues of WT and mCAT transgenic C57BL/6J mice. Data are means ± SD of at least three mice per group. (E) Summary of the relative abundance trends in the gut microbiota community and ROS abundance changes. *P < 0.05, **P < 0.01, and ***P < 0.001 by linear mixed-effects models (A), generalized linear mixed-effects models (B), or Student’s t test (C and D).

Tables

  • Table 1 Mouse models.

    For each of the mouse models used in these studies, the “MGI (Mouse Genome Informatics) strain name,” “Nuclear background,” and “Mitochondrial mutation/SNP” mtDNA sequence compared to Bl6 mtDNA reference (NC_005089) are listed. SNP, single-nucleotide polymorphism.

    ModelMGI strain nameNuclear backgroundMitochondrial mutation/SNP
    C57BL/6C57BL/6EiJC57BL/6mtDNA: ND5: C12352T (S204F)
    C57BL/6JC57BL/6JC57BL/6JnDNA: Nnt del exon7–11
    mtDNA: ND5: C12352T (S204F)
    ND6 P25L/ (C57BL/6J)B6.Cg-mt-Nd6m3Dwa/JC57BL/6JnDNA: Nnt del exon7–11
    mtDNA: ND6: G13997A (P25L); tRNAArg: 9821 insA
    mt-129 (C57BL/6J)C57BL/6J-mt129C57BL/6JnDNA: Nnt del exon7–11
    mtDNA: ND3: T9461C; tRNAArg: 9821 insA
    mt-NZB (C57BL/6J)C57Bl/6J-mtNZBC57BL/6JnDNA: Nnt del exon7–11
    mtDNA: tRNAPhe: G55A; rRNA 16S: A1353G, G1519A, G1590A, T1822C, T2201C,
    G2340A, C2525T; ND1: A2766G (Ile6Ala), T2767C (Ile6Ala), C2798T, T2814C,
    C2840T, C2934T(Arg62His), T3194C, A3260G, T3422C, T3467C, T3599C,
    A3692G;ND2: G3932A (Ala7Thr), C4123T, G4276A, T4324C, G4408A,
    A4706G(Ile265Val), C4732T, T4771C, A4885C, T4903G; tRNACys: 5205insG;
    COI: G5463A(Ala46Thr), T5552C, G5930A, T6041C, C6407T, A6470G, C6575T,
    G6620S, G6785A; COII: A7411G; ATP8: G7870A; ATP6: A8439G, T8467C,
    C8568T; COIII: T8858C, C8864T, A9137G, T9152C; tRNAGly: A9391G; ND3:
    T9461C, C9530T, C9581T, A9599G; tRNAArg: 9821 insAA; ND4L:
    G9985A(Val37Met); ND4: C10547T, A10583G, C10952A(Ile262Met);
    ND5: G11843A, C11846T, A11933C, C12353T, T12575A, A12695G,
    T12835C(Ile365Thr), A12890G, G13004A, C13444T(Thr568Ile); ND6:
    T13612C, C13689T(Val128Ile), A13781G(Ile97Ala), A13782G(Ile97Ala),
    A13837G, A13983G; CYTB: T14186C, G14211A(Ala23Thr), A14363G,
    G14642A, C14738T; control region: T15499A, C15549T, A15578T,
    C15588T, C15603T, T15657C, C15917T, A16017C, A16268G, T16272C
    mt-129/NZB (C57BL/6J)C57BL/6J-mt129/NZBC57BL/6JMix of mt-129 and mt-NZB
    mCAT (C57BL/6J)B6.Cg-Tg(CAG-OTC/CAT)4033Prab/JC57BL/6JnDNA: Nnt del exon7–11; Tg-mCAT
    mtDNA: ND5: C12352T (S204F)

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