Dysregulated Microbial Fermentation of Soluble Fiber Induces Cholestatic Liver Cancer. Dysregulated Microbial Fermentation of Soluble Fiber Induces Cholestatic Liver Cancer

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 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.

膳食可溶性膳食纤维可被肠道菌群发酵产生短链脂肪酸（short-chain fatty acids, SCFA），这类物质被广泛认为具有健康益处。据此，摄入此类可溶性膳食纤维可改善代谢综合征。然而，在成分明确的日粮中添加可溶性膳食纤维菊粉（而非不溶性膳食纤维），却会诱发黄疸型肝细胞癌（hepatocellular carcinoma, HCC）。该类肝细胞癌的发生依赖于肠道菌群，可在多种菌群失调小鼠品系中观察到，但在无菌小鼠及抗生素处理小鼠中并未出现。此外，给野生型（wild-type, WT）小鼠饲喂菊粉富集型高脂日粮，可同时诱发菌群失调与肝细胞癌。菊粉诱导的肝细胞癌进展过程为：早期出现胆汁淤积、肝细胞死亡，随后肝脏发生中性粒细胞性炎症。通过药物抑制发酵过程或耗竭发酵菌，可显著降低肠道短链脂肪酸水平并预防肝细胞癌的发生。使用考来烯胺阻止胆汁酸重吸收，同样可对该类肝细胞癌起到保护作用。综上，尽管可发酵膳食纤维具有诸多益处，但在食品中富集此类膳食纤维仍需格外谨慎，因其可能增加肝细胞癌的发病风险。