Dysregulated Fermentation of Soluble Fiber May Induce Liver Cancer

The gut microbiota benefits the host in part via metabolism of dietary fiber into valuable nutrients. Insoluble fiber resists fermentation, but soluble fiber (such as inulin) is fermented into short-chain fatty acids (SCFA), which have a beneficial metabolic effect. Disruption of the gut microbiota can lead to chronic inflammation, and mice lacking toll-like receptor 5 (TLR5) are at increased risk for developing microbiota-dependent colitis and inflammation-associated metabolic syndrome. Singh, Yeoh, Chassaing, and colleagues aimed to determine if soluble fiber might ameliorate the microbial dysbiosis and metabolic syndrome associated with TLR5 deficiency. Unexpectedly, enriching the diet of the mice with inulin induced hepatocellular carcinoma (HCC) in these innate immune-deficient mice despite improving glycemic control and reducing adiposity. The inulin diet–induced HCC was associated with hepatic inflammation and was not specific to TLR5 deficiency, but was triggered in other innate immune-dysregulated mice (including TLR4- and lipcalin-2–deficient mice). Other soluble fibers (such as pectin and fructooligosaccharides) had a similar HCC-promoting effect, but nonfermentable or insoluble fiber did not promote HCC. HCC development in TLR5-deficient mice was associated with alterations in gut microbiota (dysbiosis), with an increase in fiber-fermenting species. The susceptibility of TLR5-deficient mice to inulin-induced HCC was dependent on dysbiotic microbiota. Microbial transfer from TLR5-deficient mice rendered wild-type mice susceptible to HCC, whereas microbial ablation with broad-spectrum antibiotics prevented HCC development. Inulin-induced tumorigenesis was initiated by early-onset cholestasis that resulted in hepatocyte apoptosis, neutrophil infiltration, and liver inflammation. Tumorigenesis could be blocked by inhibition of fermentation, which resulted in reduced intestinal SCFA. Collectively, these findings suggest that enriching processed foods with fermentable fiber may increase the risk of HCC.

Singh V, Yeoh BS, Chassaing B, Xiao X, Saha P, Aguilera Olvera R, et al. Dysregulated microbial fermentation of soluble fiber induces cholestatic liver cancer. Cell 2018;175:679–94.e22.

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