Bioengineering a Probiotic to Bloom During Colonic Inflammation Promotes Reliable Efficacy in Translational Models of...

Area of Science:

• Microbiome therapeutics
• Gut microbiome engineering
• Inflammatory Bowel Disease (IBD) research

Background:

• Emerging gut microbiome research highlights potential for microbial therapeutics in IBD.
• Current microbial therapies, including E. coli Nissle 1917 (EcN), show limited efficacy in active colitis due to poor colonization.
• Engineered EcN (EcN::ttr) with the ttr operon utilizes tetrathionate, an inflammation byproduct, as fuel to enhance colonization during colitis.

Purpose of the Study:

• To bioengineer EcN with the ttr operon (EcN::ttr) to enhance colonization and therapeutic efficacy during active colitis.
• To evaluate the therapeutic potential of EcN::ttr in preclinical models of inflammatory bowel diseases.
• To elucidate the mechanisms underlying EcN::ttr's therapeutic effects, including its impact on the gut microbiome and host immune responses.

Main Methods:

• Assessed EcN::ttr efficacy in murine models of acute DSS and chronic mucin 2-deficient colitis.
• Investigated the role of IL-10 in EcN::ttr's protective effects using IL-10-deficient mice.
• Examined EcN::ttr's impact on human colonoids, focusing on barrier protein modulation.

Main Results:

• EcN::ttr demonstrated superior amelioration of colitis compared to EcN and 5-aminosalicylate.
• EcN::ttr bloomed during inflammation, promoting IL-10-dependent immunoregulatory responses and reducing leukocyte infiltration.
• Treatment with EcN::ttr led to enhanced gut microbiome function, increased butyric acid, reduced bacterial translocation, and improved ZO-1 organization.

Conclusions:

• Bioengineering EcN with the ttr operon provides a robust therapeutic effect during colitis, serving as a proof-of-concept.
• EcN::ttr exhibits enhanced colonization in inflamed guts, positioning it as a potential novel microbiome therapeutic for IBD.