Studies by an international research team have demonstrated how triclosan (TCS), an antimicrobial found in toothpaste, toys, and thousands of other products, can trigger gut inflammation. The research, led by scientists at the University of North Carolina (UNC) at Chapel Hill, the University of Massachusetts Amherst, and Hong Kong Baptist University, identified the bacteria, and specific enzymes, that trigger triclosan’s harmful effects.
Their experiments in mice also suggested that these bacterial enzymes can be blocked from driving intestinal damage, and offer up new clues about the potential management of inflammatory bowel disease (IBD), a condition that can be managed for long periods of time, but then may flare up, seemingly out of nowhere. “By identifying the culprit bacteria, new approaches could be developed for the diagnoses, prevention, and treatment of inflammatory bowel diseases,” said Matthew Redinbo, PhD, a chemistry and microbiology professor at the UNC-Chapel Hill College of Arts & Sciences and UNC School of Medicine. Redinbo and colleagues reported on their findings in Nature Communications, in a paper titled, “Microbial enzymes induce colitis by reactivating triclosan in the mouse gastrointestinal tract,” in which they concluded that their results “… suggest that the safety of TCS and related compounds should be reconsidered given their potential for intestinal damage.”
The incidence and prevalence of IBD have risen dramatically in recent decades, the authors noted, and by 2015, an estimated ~1.3% of adults in the United States (~3 million people) were diagnosed with IBD, a figure that represents about a 50% increase from 1999. IBD can severely impact on quality of life, but there is no cure, and current treatments can have serious side effects. “More alarmingly, IBD patients have increased risk of developing colorectal cancer,” the team continued.
While an increase in IBD prevalence has been linked to exposure to environmental chemicals, the potential mechanisms involved aren’t clear. TCS is an antimicrobial ingredient that is present in more than 2,000 consumer and industrial products and is detected in ~75% of urine samples tested in the United States, the authors continued. Triclosan used to be widely available in antibacterial soaps marketed to consumers. But in 2016, the FDA ordered it removed from handwashing products used in homes and hospital settings because of concerns it contributed to bacterial resistance. However, the compound remains ubiquitous as an ingredient added to cosmetics, yoga mats, and other athletic clothes and gear to reduce bacterial contamination. It’s also routinely used in many toothpastes—with FDA approval—since it has been found to prevent gingivitis.
Triclosan is also a “ubiquitous environmental contaminant” and one of the top 10 river pollutants, the authors continued. “Health problems connected to TCS include increased risks of allergies and asthma, altered immune responses, disruption of endocrine functions, and increased development of antibiotic resistance.” The team has also previously shown that exposure to TCS, at human-relevant doses, increased the severity of colitis and exaggerated the development of colitis-associated colorectal cancer in mouse models. “This finding supports that TCS could be a potential risk factor for IBD and associated diseases, though further studies are needed to determine its impacts in human populations.”
Triclosan doesn’t cause colonic inflammation in germ-free mice, and toxicity is dependent on the presence of gut microbiota, but the mechanisms involved aren’t known. Previous studies have shown that the compound is rapidly metabolized by the body’s tissues, including the liver, into a biologically inactive glucuronide-conjugated metabolite, TCS-glucuronide (TCS-G), which is thought to be quickly eliminated from the body. The researchers hypothesized that gut microbial enzymes may act on key TCS metabolites in the colon, leading to unique gut metabolic profiles that are related to reactivation of TCS in the gut, which results in subsequent gut toxicology.
For their newly reported studies, the investigators took a closer look at the changes caused in the gut’s microbiota population. Using a range of in vitro, ex vivo, and in vivo experimental approaches, the team connected specific gut microbial enzymes—notably gut microbial beta-glucuronidase (GUS) proteins—with triclosan, and showed that these enzymes, and specifically Loop 1 and FMN-binding GUSs, were most effective at converting TCS-G to TCS in vitro. The enzymes effectively act to mediate colonic reactivation of TCS from its inactive metabolite, and so drive triclosan to wreak havoc in the gut. Studies in mice exposed to TCS confirmed that while the dominant compound in most of the animals’ tissues was TCS-G, in the gut the dominant compound was free TCS. “Using a combination of approaches including in vitro culturing of gut bacteria, antibiotic-mediated suppression of gut bacteria in vivo, and germ-free mice, we found that gut microbiota converts TCS-G to TCS in the colon and therefore contribute to the unique metabolic profile of TCS in the colon,” they added.
Knowing which bacterial proteins were the culprits, the team used a microbiome-targeted inhibitor to block triclosan processing in the gut. Blocking this process in mice prevented damage to the colon and symptoms of colitis. “We showed that GUSi effectively inhibited GUS-mediated TCS-G processing in vitro and ex vivo, with little effect on commensal microbes, growth of mammalian intestinal cells, or activity of mammalian GUS enzyme,” the team noted. “These findings support that GUSi is highly selective toward the gut microbial GUS enzymes … supporting an essential role of specific microbial proteins in TCS toxicity.”
TCS metabolic profiling of stool and urine samples from human participants from a previous study also showed that after using TCS-containing products, the individuals’ urine samples contained primarily TCS-G, while the stool samples contained primarily free TCS. Collective data from the human studies thus “… establish that the human gut exhibits a unique TCS metabolic profile compared to that found in the urine and contains a high abundance of free TCS,” the authors noted.
Their results, they commented, also showed that the fecal bacteria from different human subjects had a different abundance of the Loop-1 GUS, leading to varied capacities to convert TCS-G to TCS. “While future studies are needed to determine whether individuals with specific microbial GUS activities are more susceptible to the adverse effects of TCS exposure, such studies could chart the metabolic individuality of TCS and clarify the potential toxic effects of TCS on human health,” they concluded. “More importantly, these studies will help to establish gut microbial enzymes as potential predictive markers for environmental toxicology.”
