Metformin protects against Clostridioides difficile infection by modulating both host and microbes

Clostridioides difficile (C. difficile) is the most common cause of hospital-acquired infection. The current treatments of C. difficile infection (CDI) with antibiotics are plagued by high rates of CDI recurrence and antibiotic resistance. Herein, we discovered that metformin-a safe, inexpensive, and FDA-approved antidiabetic drug, prevents CDI, by reducing microbial translocation from gut to systemic organs via promoting gut barrier functions such as increasing mucin and tight junction proteins. Metformin also beneficially modulates the gut microbiota and suppresses C. difficile spore germination, vegetative cell growth, and toxin production, resulting in dampened CDI load. Unbiased global metabolomics analyses revealed that metformin increases the accumulation of choline in C. difficile cells, which in turn inhibits bacterial growth and toxin production. These results indicate that metformin ameliorates CDI by one hand strengthening gut barriers in the host and the other weakening bacterial growth and toxicity; thus, can be an ideal candidate to be re-purposed for prevention of CDI and its recurrence.