Triclosan is an antimicrobial compound that is widely used in consumer products such as hand soaps, toothpastes, athletic wear, and children’s toys. Because of its extensive use, most Americans are routinely exposed to this compound; however, its effects on human health remain largely understudied. Recent work unveiled that triclosan exposure increases the severity of colitis and colon cancer in mouse models, indicating that the compound could be deleterious to the gut lining and therefore may be a risk factor for inflammatory bowel disease. In this study, we determine that a specific class of gut microbial enzymes, beta-glucuronidases (GUS), produces the gut toxicity of triclosan. Through in vitro and ex vivo techniques, we pinpoint that two structural classes of GUS enzymes, Loop 1 and FMN-binding GUSs, are responsible for triclosan processing. From further structural analyses, we unravel the molecular motifs necessary for triclosan metabolism by these GUS enzymes. Finally, using a targeted GUS inhibitor, we demonstrate that inhibition of these gut microbial GUS enzymes is sufficient to alleviate triclosan-induced colitis in vivo. Our results establish the relationship between the gut microbiome and triclosan-induced gut toxicity and identify GUS enzymes as a potential therapeutic target to alleviate colitis.

Inhibition of gut microbial beta-glucuronidases alleviates triclosan induced colitis

ACS Fall 2021

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