Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10−/− mice

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The composite human microbiome of Western populations has probably changed over the past century, brought on by new environmental triggers that often have a negative impact on human health1. Here we show that consumption of a diet high in saturated (milk-derived) fat, but not polyunsaturated (safflower oil) fat, changes the conditions for microbial assemblage and promotes the expansion of a low-abundance, sulphite-reducing pathobiont, Bilophila wadsworthia2. This was associated with a pro-inflammatory T helper type 1 (TH1) immune response and increased incidence of colitis in genetically susceptible Il10−/−, but not wild-type mice. These effects are mediated by milk-derived-fat-promoted taurine conjugation of hepatic bile acids, which increases the availability of organic sulphur used by sulphite-reducing microorganisms like B. wadsworthia. When mice were fed a low-fat diet supplemented with taurocholic acid, but not with glycocholic acid, for example, a bloom of B. wadsworthia and development of colitis were observed in Il10−/− mice. Together these data show that dietary fats, by promoting changes in host bile acid composition, can markedly alter conditions for gut microbial assemblage, resulting in dysbiosis that can perturb immune homeostasis. The data provide a plausible mechanistic basis by which Western-type diets high in certain saturated fats might increase the prevalence of complex immune-mediated diseases like inflammatory bowel disease in genetically susceptible hosts.

At a glance


  1. Saturated MF-induced colitis is associated with bloom of B. wadsworthia in Il10-/- mice.
    Figure 1: Saturated MF-induced colitis is associated with bloom of B. wadsworthia in Il10−/− mice.

    ag, Samples from SPF C57BL/6 (a, g) (n = 6 per group) and SPF Il10−/− mice (bg) fed MF, PUFA or LF for 24 weeks (n = 20 per group). a, Phyla representation shown for LF, PUFA and MF with means±s.e.m. *P<0.05 compared to LF, P<0.05 compared to PUFA and LF. b, Gross incidence of colitis. c, Representative colon lengths (top) and haematoxylin and eosin staining of distal colon (bottom). Scale bars, 400μm. d, Blinded histological colitis scores25. e, Distal colonic mucosal cytokines determined by ELISA. f, Principal coordinates analysis (PCoA) plot of the UNIFRAC metric matrix. PC, principal coordinate. g, qPCR of caecal content dsrA (normalized to LF diet).

  2. B. wadsworthia mono-association in GF Il10-/- mice can only be established with consumption of MF diet, resulting in a TH1 immune response and development of colitis.
    Figure 2: B. wadsworthia mono-association in GF Il10−/− mice can only be established with consumption of MF diet, resulting in a TH1 immune response and development of colitis.

    ac, Samples from GF Il10−/− mice±mono-association with 108c.f.u. B. wadsworthia (Bw) maintained on LF, PUFA or MF for 5 weeks (n = 5 per group). a, c.f.u. counts of cultured caecal-derived B. wadsworthia. b, Blinded histological colitis scores. c, IFN-γ production by CD4+ T cells in MLNs. d, IFN-γ production by MLNs from GF C57BL/6 and Il10−/− mice colonized with either B. wadsworthia or L. murinus (Lacto) and restimulated ex vivo with pure culture lysate from the respective bacterium. e, In vitro CD4+ T-cell differentiation assay. Left, IL-12p40 produced by dendritic cells challenged with pure lysates from B. wadsworthia, L. murinus or Alistipes (Alist). Unstim., unstimulated. Data represent pooled values from MLN dendritic cells and splenic dendritic cells in the presence of retinoic acid/TGF-β. Right, IFN-γ production by CD4+ T cells stimulated with supernatants from the bacteria-challenged dendritic cells. Data shown represent one out of two assays, performed in triplicate.

  3. Induction of TC bile acid following consumption of MF promotes bloom of B. wadsworthia both in vitro and in SPF Il10-/- mice, resulting in colitis.
    Figure 3: Induction of TC bile acid following consumption of MF promotes bloom of B. wadsworthia both in vitro and in SPF Il10−/− mice, resulting in colitis.

    a, TC content of gall bladder aspirates from Il10−/− mice consuming LF, PUFA or MF for 5 weeks. b, Growth curve of B. wadsworthia in media containing gall bladder aspirates. cg, Samples from SPF Il10−/− mice gavaged with PBS, TC or GC daily for 21 days while maintained on LF diet (n = 8 per group). c, Phyla representation with bloom of B. wadsworthia in the TC group with means±s.e.m. *P<0.05 compared to PBS and GC. d, Relative abundance of dsrA in caecal contents (by qPCR and normalized to LF diet). e, f, Blinded histological colitis scores (e) and haematoxylin and eosin staining of distal colon (f). Scale bars, 400μm g, IFN-γ production in MLNs.

  4. Mono-association with B. wadsworthia in GF Il10-/- mice is successful only if accompanied by TC gavage.
    Figure 4: Mono-association with B. wadsworthia in GF Il10−/− mice is successful only if accompanied by TC gavage.

    ac, Samples from GF Il10−/− mice fed LF±mono-association with B. wadsworthia (Bw) followed by daily gavage with PBS, GC or TC for 21 days (n = 5 per group). a, Robust B. wadsworthia growth when re-isolated from caecal content of TC-fed GF mice (black film in TC plate indicates H2S production), and c.f.u. counts of caecal-derived B. wadsworthia. b, Blinded histological colitis scores. c, IFN-γ production in MLN CD4+ T cells determined by intracellular staining. d, Proposed experimental model.

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  1. Department of Medicine, Section of Gastroenterology, The University of Chicago, Knapp Center for Biomedical Discovery, 900 East 57th Street, Chicago, Illinois 60637, USA

    • Suzanne Devkota,
    • Yunwei Wang,
    • Mark W. Musch,
    • Vanessa Leone,
    • Hannah Fehlner-Peach,
    • Anuradha Nadimpalli,
    • Bana Jabri &
    • Eugene B. Chang
  2. Institute for Genomics and Systems Biology, Argonne National Laboratory, 9700 South Cass Avenue, Argonne, Illinois 60439, USA

    • Dionysios A. Antonopoulos


S.D. and E.B.C. were involved in all aspects of this study, especially in the development of the hypothesis, experimental plan and data analysis. Y.W., M.W.M., V.L., H.F.-P. and A.N. helped perform the experiments. D.A.A. and B.J. provided critical feedback and expertise and assisted in the analysis of data.

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The authors declare no competing financial interests.

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Data have been deposited in GenBank under accession numbers JQ890637–JQ894320.

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