Antimicrobial additive triclosan exacerbates inflammation and colitis-associated colon cancer in mice

Mice models are widely used to assess the impact of exposure to environmental factors such as chemicals, drugs or infectious agents on host homeostasis through modulation of the gut microbiota.

A new study, led by Dr. Guodong Zhang from the University of Massachusetts (USA), has found that exposure to triclosan increases colonic inflammation and colitis-associated colon tumorigenesis in mice.

Triclosan (TCS) is a widely used antimicrobial additive found in products such as toothpaste, cosmetics, kitchenware and toys. Treating mice with a diet containing 10 and 80 ppm TCS for 3 weeks increased plasma concentrations of both TCS and its major metabolite TCS glucuronide. TCS exposure also led to enhanced systemic and low-grade colonic inflammation, reported through increased spleen weight, higher plasma concentration of proinflammatory cytokine interleukin (IL)-6 and enhanced gene expression of IL-6 and exaggerated crypt damage in the colon. Exposure to TCS—even at low-doses (5 to 10 ppm in diet)—also increased colitis in dextran sodium sulfate (DSS)-induced inflammatory bowel disease (IBD) and Il-10/ mice models, which are both well-established models used in our understanding of IBD. These findings highlight the IBD-promoting effect of triclosan in mice.

TCS exposure also increased colon tumorigenesis and tumor inflammation in a mouse model of colorectal cancer when compared with vehicle-treated (dimethyl sulfoxide) mice. The mechanisms involved consisted of an increased average tumor number and size, the infiltration of immune cells into colon tumors, increased plasma concentrations of IL-6 and tumor necrosis factor-a (TNF-a), and their gene expression in colon tumors, along with increased colonic expression of several genes involved in promoting colon carcinogenesis via the Wnt signaling pathway.

The researchers also studied the impact on the gut microbiota of treatment with 80 ppm TCS in diet for 3 weeks. TCS exposure altered gut microbiota composition, causing up to a 75% reduction in the abundance of Bifidobacterium. These bacteria have anti-inflammatory effects by inhibiting lipopolysaccharide-induced nuclear factor-kappaB activation. TCS also inhibited the growth of Bifidobacterium infantis 272 in vitro.

It is worth mentioning that in germ-free mice, the proinflammatory effects of TCS treatment were attenuated, suggesting the gut microbiota’s involvement in TCS effects in vivo.

Plasma from the TCS-treated DSS mice had a higher concentration of LPS and showed enhanced activation of Toll-like receptors 4, which mediate innate immunity and interactions between host cells and our gut microbiota. The fact that TCS effects on IL-6 gene expression were not observed in Tlr4/ confirm that TLR4 may mediate the pro-colitis effect of TCS. These results could be partially mediated by an altered intestinal barrier function, as TCS exposure increased leakage of orally-administered fluorescein isothiocyanate-dextran from the gut into the circulation and altered the expression of the colonic protein Occludin, which is involved in maintaining intestinal permeability. Together, these data show how exposure to TCS increases activation of TLR4 in vivo by increasing the circulating concentrations of bacterial products such as LPS and involving a dysfunction of the intestinal barrier function.

In conclusion, these results show that in mice, exposure to TCS exacerbates colonic inflammation and is related to colon tumorigenesis by modulating the gut microbiota and TLR4 signaling. Further safety studies are needed to balance whether the current doses of TCS used in consumer products need to be reassessed with regards to human health.

 

Reference:

Yang H, Wang W, Romano KA, et al. A common antimicrobial additive increases colonic inflammation and colitis-associated colon tumorigenesis in mice. Sci Transl Med. 2018; 10(443). doi: 10.1126/scitranslmed.aan4116.

Andreu Prados
Andreu Prados
Andreu Prados holds a Bachelor of Science Degree in Pharmacy & Human Nutrition and Dietetics. Science writer specialised in gut microbiota and probiotics, working also as lecturer and consultant in nutrition and healthcare. Follow Andreu on Twitter @andreuprados