Dysregulated Microbial Fermentation of Soluble Fiber Induces Cholestatic Liver Cancer

Abstract

SUMMARY Dietary soluble fibers are fermented by gut bacteria into short-chain fatty acids (SCFA), which are considered broadly health-promoting. Accordingly, consumption of such fibers ameliorates metabolic syndrome. However, incorporating soluble fiber inulin, but not insoluble fiber, into a compositionally defined diet, induced icteric hepatocellular carcinoma (HCC). Such HCC was microbiota-dependent and observed in multiple strains of dysbiotic mice but not in germ-free nor antibiotics-treated mice. Furthermore, consumption of an inulin-enriched high-fat diet induced both dysbiosis and HCC in wild-type (WT) mice. Inulin-induced HCC progressed via early onset of cholestasis, hepatocyte death, followed by neutrophilic inflammation in liver. Pharmacologic inhibition of fermentation or depletion of fermenting bacteria markedly reduced intestinal SCFA and prevented HCC. Intervening with cholestyramine to prevent reabsorption of bile acids also conferred protection against such HCC. Thus, its benefits notwithstanding, enrichment of foods with fermentable fiber should be approached with great caution as it may increase risk of HCC.

Perturbed Microbial Ecology in Myasthenia Gravis: Evidence from the Gut Microbiome and Fecal Metabolome

“…[7][8][9] Previous studies have demonstrated altered gut microbiome to be associated with several complex diseases such as obesity, diabetes, and cancer. [10][11][12] Recent emerging evidence shows that gut microbiome changes were linked with onset of disorders including stroke, epilepsy, Parkinson's disease, depression, and schizophrenia via the "microbiota-gut-brain" (MGB) axis. [13][14][15][16][17] Thus it is becoming increasingly clear that the gut microbiome is a central regulator of host immune homeostasis, [9,18] whose dysregulation may participate in the onset of central (e.g., multiple sclerosis) and peripheral (e.g., rheumatoid arthritis) autoimmune diseases.…”

Soluble Fibers Improve Metabolic Syndrome but May Cause Liver Disease and Hepatocellular Carcinoma

“…Accordingly, it is conceivable that soluble fiber may not only exert a positive effect on liver diseases by improving obesity and diabetes, but also by improving gut health and normalizing the disturbed gut‐liver axis. A recent study by Singh et al, published in Cell , puts this concept into question . Using diets supplemented with soluble fibers such as inulin, pectin, fructooligosaccharides (FOS) or insoluble fibers such as cellulose, the researchers found that diets high in soluble fibers induced liver injury, cholestasis, and HCC when given to mice with preexisting dysbiosis, such as Toll‐like receptor 5 (Tlr5) knockout (Tlr5ko) mice.…”

“…With millions of people consuming food supplements containing soluble fibers such as inulin and pectin, the most important question is whether these findings, exclusively established in mouse studies, have human relevance, and whether people who consume high amounts of soluble fibers, in particular inulin, may increase their risk of developing liver disease and HCC. The majority of experiments in the study by Singh et al were performed in Tlr5ko mice that were fed a diet with amounts of inulin that are far in excess of the recommended doses for patients . Singh et al addressed these points to some degree by confirming that cholestasis and HCC development were observed in models of dysbiosis other than Tlr5ko mice, and also when using types of soluble‐fiber–enriched diets such as pectin and FOS and a diet containing only 2.5% inulin .…”

“…The majority of experiments in the study by Singh et al were performed in Tlr5ko mice that were fed a diet with amounts of inulin that are far in excess of the recommended doses for patients . Singh et al addressed these points to some degree by confirming that cholestasis and HCC development were observed in models of dysbiosis other than Tlr5ko mice, and also when using types of soluble‐fiber–enriched diets such as pectin and FOS and a diet containing only 2.5% inulin . Whereas the combination of 7.5% inulin and the HFD dysbiosis model still resulted in ≈10% HCC incidence and the 2.5% inulin diet in Tlr5ko mice in ≈18% HCC incidence, the researchers did not test the more realistic setting in which HFD is combined with 2.5% inulin.…”

“…With recommended daily doses of inulin ranging from 10 to 40 g, a 2.5% inulin diet is closer to human relevant concentrations. Likewise, dysbiosis induced by HFD seems a more physiological context than dysbiosis in Tlr5ko mice, which not only display variable dysbiosis depending on the animal facility, but also have a defect in mucosal immunity resulting in increased bacterial translocation . Therefore, testing the combination of lower inulin concentrations, such as a 2.5% inulin‐containing diet in mice fed HFD, would likely be the most human‐relevant experiment in mice and is likely to yield a much lower incidence of HCC and possibly no HCC at all.…”