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This antibacterial ingredient in toothpaste can trigger intestinal inflammation

Nature sub-journal: This antibacterial ingredient in toothpaste can trigger intestinal inflammation



Nature sub-journal: This antibacterial ingredient in toothpaste can trigger intestinal inflammation

Speaking of the chemical term triclosan (TCS) , it is still very unfamiliar to most Chinese consumers. Few ordinary people know that triclosan is a broad-spectrum antibacterial agent that is widely added to daily chemicals such as toothpaste, soap, deodorant, mouthwash, shaving cream, etc. Among them, toothpaste is the “big player” of adding triclosan.

In 2016, the U.S. Food and Drug Administration (FDA) ordered the removal of triclosan from handwashing products used in home and hospital settings, largely because of concerns that triclosan could lead to more resistant bacteria. In fact, there has been an ongoing debate about the safety of triclosan, with news of doubts about the safety of triclosan toothpaste as early as 2005.

On January 10, 2021, an international research team led by the University of North Carolina at Chapel Hill, the University of Massachusetts Amherst, and Hong Kong Baptist University published in Nature Communications titled: Microbial enzymes induce colitis by reactivating triclosan In a research paper in the mouse gastrointestinal tract , this study in mice demonstrates how triclosan triggers intestinal inflammation .

This antibacterial ingredient in toothpaste can trigger intestinal inflammation

Unique triclosan metabolic profile in the mouse gut

The researchers first sought to determine whether the gut exhibits a different metabolic profile of triclosan than other tissues.

Mice were treated with 80 ppm triclosan (TCS) for 4 weeks, and then the concentrations of TCS and its metabolites in a series of mouse tissues were analyzed using LC-MS/MS.

The results showed that the major TCS-related compound found in liver, bile, heart and small intestine after TCS exposure was the metabolite TCS-G .

In contrast, the mouse cecum and colon were dominated by free TCS .

The TCS metabolites found in the 4th chyme of the mouse small intestine were 36.9% free TCS, 55.4% TCS-G and 7.7% TCS-sulfate (TCS sulfate-bound metabolite) ; whereas the fecal content showed 99.1% Free TCS, only 0.7% TCS-G and 0.2% TCS-sulfate.

These results suggest that the colon has a distinct TCS metabolic profile and uniquely contains almost universal free TCS compared to other tissues .

This antibacterial ingredient in toothpaste can trigger intestinal inflammation

Unique triclosan metabolic profile in the human gut

To broaden our understanding of the TCS metabolic profile in the gut, we next analyzed TCS metabolism in human subjects.

The researchers used urine and stool samples from a previous study in which human subjects were recruited to undergo a washout period (without using a product containing TCS) and then randomly assigned to use toothpaste with or without TCS group for up to four months.

The researchers analyzed the metabolic profile of TCS in TCS-exposed human subjects. LC-MS/MS showed that in all subjects tested for TCS exposure, the predominant compound in fecal samples was free TCS, while the predominant compound in urine samples was TCS-G .

The mean molar ratio of TCS, TCS-G, and TCS-sulfate in human feces was 99.2%:0.8%:0.0% and in urine was 1.6%:98.4%:0.0%.

Taken together, these results suggest that the human gut exhibits a unique TCS metabolic profile and contains a high abundance of free TCS .

This antibacterial ingredient in toothpaste can trigger intestinal inflammation

The gut microbiota converts TCS-G to TCS in the colon

Experimental data show that the concentration of TCS increases while the concentration of TCS-G decreases from the proximal to distal regions of the gut.

Therefore, we hypothesize that the gut microbiota is involved in the conversion of TCS-G to TCS, leading to the accumulation of TCS in the lower gastrointestinal tract.

To test this hypothesis, the study used a variety of methods, including in vitro culture of gut bacteria, antibiotic-mediated in vivo inhibition of gut bacteria, and the use of germ-free mouse models to examine the role of gut microbiota in TCS colonic metabolism effect.

First, the researchers cultured gut bacteria under anaerobic conditions and tested whether the cultured bacteria could convert TCS-G to TCS in vitro, finding that fecal bacteria from mice and humans were able to catalyze TCS at significantly higher levels than controls. -G Conversion to TCS.

These results support the conclusion that anaerobic cultured gut bacteria can catalyze the deglucuronidation of TCS-G to produce TCS .

To further examine the role of gut bacteria in the colonic metabolism of TCS, the time-dependence of antibiotic effects was examined, mice were pretreated with or without an antibiotic cocktail and then received TCS via a one-time oral gavage, and then after treatment The metabolic profile of TCS was examined at 4, 8, 12 and 24 hours.

Antibiotic inhibition of gut bacteria was found to decrease TCS and increase TCS-G in mouse colonic chyme in a time-dependent manner.

This finding further supports the conclusion that gut bacteria contribute to the conversion of TCS-G to TCS in the colon.

Finally, we further examined the role of gut microbiota in colonic metabolism of TCS using a germ-free mouse model.

Common or germ-free mice were treated with TCS , and colonic TCS metabolic profiles were analyzed at 4 and 8 hours.

The results showed that germ-free mice exhibited decreased TCS and increased TCS-G in their colonic chyme compared with normal mice, which was consistent with the results of antibiotic experiments.

These results support the conclusion that commensal microorganisms convert TCS-G to TCS in the colon .

This antibacterial ingredient in toothpaste can trigger intestinal inflammation

β-Glucuronidase (GUS) ortholog converts TCS-G to TCS

Next, the researchers sought to find the specific gut microbial enzymes that convert TCS-G to TCS.

Since gut β-glucuronidase (GUS) is capable of converting a variety of glucuronidation metabolites to the corresponding glycosyl groups, it was hypothesized that gut microbial GUS homologues could catalyze the conversion of TSC-G to TCS.

Human and mouse gut microbiota have been shown to contain hundreds of unique gut microbial GUS enzymes that exhibit different substrate specificities for different glucuronides.

Previous studies have shown that microbial GUS enzymes can be divided into seven distinct branches based on active site structure and/or cofactor binding.

The researchers created 32 purified gut microbial GUS enzymes, representing seven clades, for in vitro enzymatic screening.

The researchers first screened the cleavage activity of TCS-G by coupling experiments and found that the GUS homologue bound by Loop 1 and flavin mononucleotide (FMN) was the most efficient when using the substrate TCS-G .

The detection and comparison of the conversion efficiency of different GUS enzymes from TCS-G to TCS in human feces also supports the conclusion that Loop 1 gut microbial GUS enzymes appear to be an important driver of TCS-G conversion .

Targeted inhibition of GUS enzymes abrogates the colitis-promoting effect of TCS in vivo

First, we tested the effect of a GUS inhibitor (UNC1020165224,37; GUSi) on TCS-G processing in vitro and found that it inhibited in a dose-dependent manner the purified Fp2-L1 GUS enzyme, as well as several other Loop 1 GUS enzymes Conversion of TCS-G to TCS .

More surprisingly, GUSi also inhibited the processing of TCS-G by FMN-bound GUS enzymes .

Next, the researchers tested the effect of GUSi on TCS-G processing with an in vitro fecal enzyme cocktail.

Although only two male and two female stool samples were tested here, the manner in which GUSi inhibited TCS-G processing was found to reflect the level of GUS present in each sample examined.

In particular, GUSi showed more potent inhibition of in vitro samples containing higher levels of Loop 1 GUS enzyme. These data demonstrate that GUSi blocks TCS-G processing in in vitro human fecal extracts .

Finally, we used GUSi to determine the role of gut microbial GUS enzymes in TCS-promoting colitis. We treated mice with TCS, administered 1 mg/kg GUSi with or without oral gavage, and examined the development of dextran sodium sulfate (DSS) -induced colitis in mice.

The results showed that TCS exposure increased the severity of DSS-induced colitis in mice compared with controls . However, this effect is eliminated by GUSi .

In the absence of GUSi, exposure to TCS exacerbates DSS-induced colitis : TCS treatment reduces colon length, leads to more severe crypt damage, and enhances colonic infiltration of immune cells, including CD45 + , compared to controls Leukocytes, CD45 + F4/80 + macrophages and CD45 + Gr1 + neutrophils, and expression of pro-inflammatory genes (Tnf-a, Mcp-1, Il-6, Il-17 and Il-23) in the colon Increase.

However, the colitis-enhancing effect of TCS was abolished in all measurements by co-administration of GUSi.

Thus, inhibition of gut microbial GUS enzymes abolished the colitis-enhancing effect of TCS, supporting the conclusion that GUS enzymes produced by gut bacteria are required for TCS enterotoxicity.

The present study demonstrates that gut commensal microbes mediate the metabolic activation of triclosan in the colon and drive its enterotoxicology.

Using a series of in vitro and in vivo experiments, the specific enzyme involved, beta-glucuronidase (GUS) ase, was identified.

Furthermore, targeted inhibition of the GUS enzyme abrogated the colitis-promoting effect of triclosan.

Taken together, our findings reveal the mechanisms underlying the metabolic activation of triclosan by gut microbial enzymes and its gut toxicity , and will help to better assess the individual effects of triclosan in different populations.

Triclosan is still widely added to cosmetics, yoga mats and other sports apparel and gear as a bacteriostatic agent to reduce bacterial contamination.

Because triclosan can prevent gingivitis, it is added to many toothpastes. Triclosan’s toxicity has been demonstrated before, and this new study provides a closer look at triclosan’s changes in gut microbes.

” By identifying the culprit bacteria, new approaches can be developed to diagnose, prevent and treat inflammatory bowel disease, ” said study author Matthew Redinbo .

Together, these findings suggest that the effects of triclosan and related compounds on human health should be re-evaluated, given the potential harm to the gut from triclosan and related compounds.

Paper link : This antibacterial ingredient in toothpaste can trigger intestinal inflammation

https://doi.org/10.1038/s41467-021-27762-y

This antibacterial ingredient in toothpaste can trigger intestinal inflammation

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