Dysregulated gut microbial fermentation of soluble fiber induces cholestatic liver cancer

Authors: SINGH, VISHAL - Pennsylvania State University; YEOH, BENG SAN - Pennsylvania State University; CHASSAING, BENOIT - Georgia State University; OLVERA, RODRIGO - Pennsylvania State University; XIAO, XIA - Pennsylvania State University; SAHA, PIU - Pennsylvania State University; LAPEK, JOHN - University Of California; ZHANG, LIMIN - Pennsylvania State University; ZHENG, SIYANG - Pennsylvania State University; Flythe, Michael; GONZALEZ, DAVID - Walloon Excellence In Life Sciences And Biotechnology (WELBIO); CANI, PATRICE - Walloon Excellence In Life Sciences And Biotechnology (WELBIO); CONEJO-GARCIA, JOSE - H Lee Moffitt Cancer Center; JOE, BINA - University Of Toledo; PATTERSON, ANDREW - Pennsylvania State University; GEWIRTZ, ANDREW - Georgia State University; VIJAY-KUMAR, MATAM - Pennsylvania State University

Submitted to: Cell
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/6/2018
Publication Date: 10/18/2018
Citation: Singh, V., Yeoh, B., Chassaing, B., Olvera, R.A., Xiao, X., Saha, P., Lapek, J., Zhang, L., Zheng, S., Flythe, M.D., Gonzalez, D.J., Cani, P.D., Conejo-Garcia, J.R., Joe, B., Patterson, A.D., Gewirtz, A.T., Vijay-Kumar, M. 2018. Dysregulated gut microbial fermentation of soluble fiber induces cholestatic liver cancer. Cell. 175(3):679-694. https://doi.org/10.1016/j.cell.2018.09.004.
DOI: https://doi.org/10.1016/j.cell.2018.09.004

Interpretive Summary: Agricultural scientists have a strict definition of the term fiber, but in human nutrition “fiber” includes a variety of complex carbohydrates. “Soluble dietary fiber” is generally considered beneficial for humans and animals. However, this study has revealed a potential health risk associated with inulin, a carbohydrate that is considered a “soluble dietary fiber”. Inulin itself is not digested or absorbed by animals, but microorganisms in the digestive tract can ferment it. Inulin was fed to Toll-like receptor 5- knockout mice. These mice are missing a protein that allows the mouse cells to recognize certain bacteria. When the protein is missing, the animal is immunologically compromised and prone to inflammatory bowl disease, metabolic disease and other issues. Inulin decreased the symptoms of metabolic disease in the mice, but some of the mice (~40% of males, ~20% of females) developed hepatocellular carcinomas (HCC; a type of liver cancer) and other symptoms of liver damage. The inulin diet was associated with a change in the profile of bacteria in the gut, and an increase butyric acid, a bacterial product. When the inulin in the diet was replaced with cellulose (a less digestible fiber), butyric acid did not increase and liver damage was not observed. When the inulin was replaced with high levels of butyric acid itself, liver damage was observed. In another experiment inulin was included in the diet, but the mice also received a natural antimicrobial (beta-acid from the hops plant) or a broad-spectrum antibiotic. In that case, the antimicrobials decreased butyric acid production and HCC and other liver damage were prevented. These results indicate that conversion of inulin to excessive amounts of butyric acid by gut bacteria caused liver damage and HCC in a sub-set of the Toll-like receptor 5- knockout mice.

Technical Abstract: Dietary soluble fibers (inulin, pectin and fructooligosaccharide) are fermented by gut bacteria into short-chain fatty acids (SCFAs), which are considered broadly health-promoting. Accordingly, such fibers ameliorated metabolic syndrome in mice. However, prolonged feeding of such fibers, but not the insoluble fiber cellulose, induced development of icteric hepatocellular carcinoma (HCC). Such HCC was microbiota-dependent and observed in multiple strains of dysbiotic innate immune deficient mice (Toll-like receptor 5, Toll-like receptor 4, Lipocalin-2). Furthermore, consumption of an inulin-enriched high-fat diet induced both dysbiosis and HCC even in WT mice. Pharmacological inhibition of fermentation or depletion of fermentative bacteria markedly reduced SCFAs, especially butyrate, and prevented HCC. Moreover, butyrate was directly mitogenic for cultured hepatocytes and butyrate feeding in mice induced liver fibrosis, which likely contributed to fiber-induced HCC. Thus, its beneficial aspects notwithstanding, modulation of diet to promote fermentation should be approached with great caution as it may increase risk of HCC.