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Session: President's Oral Session: Abstracts of Distinction (Oral 33)

(OR33-04-24) Short-Term Caloric Restriction Alters the Microbiome Modulating Resistance to Clostridioides difficile Infection

Tuesday, July 2, 2024
10:36 AM – 10:48 AM CT
Location:  W375D
NTAC ELPC

    Presenting Author(s)

  • Jingcheng Zhao, PhD

    Postdoctoral Fellow
    The Pennsylvania State University, Department of Biochemistry and Molecular Biology
    University Park, Pennsylvania, United States

    Disclosure(s): No relevant financial relationship(s) with ineligible companies to disclose.

    • Co-Author(s)

  • AS

    Arvid Sandforth

    Helmholtz Center Munich, German Center for Diabetes Research, Eberhard-Karls University of Tübingen, Germany

  • ST

    Shuchang Tian

    The Pennsylvania State University, Department of Biochemistry and Molecular Biology, United States

  • Peter James Turnbaugh, PhD

    Associate Professor
    University of California, San Francisco
    San Francisco, California, United States

  • RV

    Reiner Jumpertz Von Schwartzenberg

    Helmholtz Center Munich, German Center for Diabetes Research, University of Tübingen, Eberhard-Karls University of Tübingen, Germany

  • JB

    Jordan E. Bisanz

    The Pennsylvania State University, United States

Objectives: Diet is a major factor modifying the gut microbiota and our previous work has shown that a 2-month 800 kcal/day liquid diet disrupted the microbiome and modified susceptibility to C. difficile. The objective of the current study was to contrast the effects of diet processing and duration on gut microbiota and colonization resistance to C. difficile.

Methods: We conducted a randomized, cross-over study of 10 healthy individuals consuming either a liquid very-low-calorie diet or a solid-food nutritionally matched diet over 5-day intervals with a 5-day wash-out period in between. These studies were complemented by gnotobiotic mouse models for mechanistic investigation of the interaction between caloric restriction (CR), microbiome, and C. difficile infection.

Results: Both short-term liquid and solid diets had significant effects on microbiota composition with an increased impact of highly bioavailable liquid diets. Fecal microbiota from the participants was transplanted to germ-free mice which were challenged with C. difficile. Contrasting our previous results, both 5-day diets increased resistance to C. difficile infection. We next designed a caloric restriction model in conventional mice and confirmed that short, but not long-term CR, protected against C. difficile infection. To confirm these findings in a tractable model, humanized mice were randomly assigned to three CR levels (100, 60, and 30% ad libitum for 1 week and then their microbiota was transplanted into recipient diet-naive germ-free mice. Short-term CR increased C. difficile resistance in both donor and recipient animals which was robustly associated with an increase in a Bacteroides caccae strain. We isolated the representative strain of B. caccae and confirmed that the administration of B. caccae could protect against C. difficile infection in vivo. Furthermore, in vitro assays demonstrated that B. caccae could utilize mucin to survive during caloric restriction producing short-chain fatty acids.

Conclusions: Short-term CR affects gut microbiome composition and protects against C. difficile infection. This further reinforces the interplay between diet and microbiome composition in affecting host health while pointing towards new strategies for infectious disease management.

Funding Sources: NIAID (R00 AI147165), NIGMS (R35 GM151045), EXC-2124/1-03.007, and VH-NG-1619