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. 2021 Sep 7;36(10):109683.
doi: 10.1016/j.celrep.2021.109683.

Clostridioides difficile infection induces a rapid influx of bile acids into the gut during colonization of the host

Aaron G Wexler  1 , Emma R Guiberson  2 , William N Beavers  1 , John A Shupe  3 , M Kay Washington  3 , D Borden Lacy  4 , Richard M Caprioli  5 , Jeffrey M Spraggins  6 , Eric P Skaar  7
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VSports手机版 - Clostridioides difficile infection induces a rapid influx of bile acids into the gut during colonization of the host

Aaron G Wexler (VSports app下载) et al. Cell Rep. .

V体育安卓版 - Abstract

Clostridioides difficile is the leading cause of nosocomial intestinal infections in the United States. Ingested C. difficile spores encounter host bile acids and other cues that are necessary for germinating into toxin-producing vegetative cells VSports手机版. While gut microbiota disruption (often by antibiotics) is a prerequisite for C. difficile infection (CDI), the mechanisms C. difficile employs for colonization remain unclear. Here, we pioneered the application of imaging mass spectrometry to study how enteric infection changes gut metabolites. We find that CDI induces an influx of bile acids into the gut within 24 h of the host ingesting spores. In response, the host reduces bile acid biosynthesis gene expression. These bile acids drive C. difficile outgrowth, as mice receiving the bile acid sequestrant cholestyramine display delayed colonization and reduced germination. Our findings indicate that C. difficile may facilitate germination upon infection and suggest that altering flux through bile acid pathways can modulate C. difficile outgrowth in CDI-prone patients. .

Keywords: CDI; Clostridioides difficile; MALDI IMS; bile acids; enteric infection; microbiota; taurocholate V体育安卓版. .

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Figures

Figure 1.
Figure 1.. MALDI IMS reveals elevated levels of TCA in the ileal lumen of CDI mice
(A) Mass spectrum from MALDI IMS analysis of the ileal region and lumen of a CDI mouse at 3 DPI reveals over 170 analytes, with m/z 514.3 being the most abundant analyte detected. (B) MALDI IMS analysis of the ileal region and lumen of CDI or mock-infected animals at 3 DPI reveals elevated levels of m/z 514.3 in CDI mice relative to mock-infected controls normalized by total ion current. Inset: H&E stain of MALDI-imaged cryosections. (C) LC-MS/MS analysis of CDI distal small intestine tissue and lumen homogenate shows a peak at m/z 514.3, supporting the identification of m/z 514.3 in (A) and (B) as TCA.
Figure 2.
Figure 2.. CDI induces a rapid influx of primary bile acids into the gut in a manner dependent on C. difficile toxins but independent of inflammation
(A–D) Ratios of unconjugated (A and B) and taurine-conjugated (C and D) primary bile acids in the liver, ileum, and cecum of CDI versus mock-infected mice. (E) Ratios of primary bile acids in the liver, ileum, and cecum of toxin-deficient (tcdAB::CT) versus mock-infected mice at 3 DPI. (F) Ratios of primary bile acids in the liver, ileum, and cecum of DSS-treated versus untreated control mice after 2 days of treatment. Concentrations are adjusted based on sample weight (μM/g) prior to calculating LC-MS/MS-based ratios. Data are represented as mean ± standard error of the mean (SEM); DPI, days post-infection; n.d., not detected in CDI mice; #, not detected in all mice; *p < 0.05, significance determined by unpaired two-sided t tests; n = 5 mice/group.
Figure 3.
Figure 3.. The host responds to CDI-induced elevations in bile acid pools by reducing bile acid biosynthesis gene expression
(A) Schematic of key steps in the bile acid biosynthesis pathway in the murine liver. CYP7A1 controls bile acid pool size, CYP8B1 determines the ratio of cholate to chenodeoxycholate and muricholate, and BAAT conjugates bile acids with taurine or glycine. (B–D) Expression of Cyp7a1 (B), Cyp8b1 (C), and Baat (D) in the livers of CDI mice relative to mock-infected mice over time. All expression values were first normalized to β-actin expression. Data plots show mean ± SEM; significance determined by unpaired two-sided t tests; n = 5 mice/group.
Figure 4.
Figure 4.. Elevated bile acid pool size is necessary for rapid host colonization and spore germination
CDI mice provided cholestyramine in their diet display delayed colonization relative to CDI mice provided a control diet without cholestyramine. (A) Vegetative cell counts from fecal samples collected over time. (B) CDI mice on a cholestyramine diet display delayed colonization compared with CDI mice on a control diet. (C and D) Spore counts and vegetative cell counts (A) from fecal samples collected over time (C) were used to determine the ratio (D) of vegetative cells to spores in cholestyramine and control mice. (E) CDI mice on a cholestyramine diet carry similar levels of primary bile acids in their ilea and ceca compared with CDI mice on a control diet at 3 DPI. Data are represented as mean ± SEM; n.d., not detected; #, not detected in all mice; *p < 0.05, significance determined by unpaired two-sided t tests; n = 10 mice/group.
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