Gut Bacteria Link Dietary Fiber with Liver Cancer

Many of the processed foods we find on grocery store shelves have been loaded up with highly refined soluble fibers such as inulin, a popular probiotic that recently received approval from the FDA to be marketed as health-promoting.

But a new study from The University of Toledo’s (UT) College of Medicine and Life Sciences is raising serious questions about whether the risks of adding refined fiber to processed foods may significantly outweigh the benefits.  The researchers have surprisingly found that mice developed liver cancer (hepatocellular carcinoma; HCC) when fed on diets fortified with refined soluble fibers.

The research, headed by Matam Vijay-Kumar, Ph.D., director of the UT Microbiome Consortium and associate professor in the UT department of physiology and pharmacology, was originally designed to investigate whether a diet enriched with inulin might help to combat obesity-related health issues in mice, and the results did show that the inulin-rich diet helped to reduce obesity levels in a mouse model. But the experiments also found a clear association between dietary inulin and the development of liver cancer in mice that had altered levels of gut bacteria that could ferment this type of refined soluble fiber.

The discovery puts a question mark over the practice of adding refined fibers to processed foods, the authors suggest. “The results shook us,” comments Dr. Vijay-Kumar. Reporting their findings in Cell (“Dysregulated microbial fermentation of soluble fiber induces cholestatic liver cancer”) the authors conclude, “… benefits notwithstanding, enrichment of foods with fermentable fiber should be approached with great caution as it may increase risk of HCC.”

Westernized diets typically include increased amounts of processed foods that are high in fat and sugar, in parallel with reduced consumption of grains, fruits, and vegetables that are naturally high in fiber, the authors explain. This dietary trend has been linked with the well-documented increase in the prevalence of obesity and related metabolic diseases. “One seemingly logical and practical approach to counter some of the unhealthy effects of ’western diets’ might be to enrich processed foods with plant-derived fibers,” the researchers suggest.

Dietary fiber comes in two basic forms, soluble fiber, which can be fermented by gut bacteria, and insoluble fiber, which is not fermentable. Inulin is a soluble prebiotic fiber that is metabolized by the gut microbiota to produce short-chain fatty acids (SCFA), and SCFAs have been found to play key roles in gut and immune system health. “Such effects likely contribute to inulin’s beneficial metabolic effects, which include reducing adiposity and improving glycemic control,” the authors note.

They set up a study to see if the refined, fermentable fiber inulin and the resulting SCFAs generated might prove effective against metabolic syndrome in a mouse model of obesity and metabolic syndrome. The results confirmed that adding inulin to their diets did reduce adiposity in about 40% of animals, compared with adiposity observed in mice fed a grain-based diet. The inulin-fortified diet was also linked with improved glycemic control. However, adding inulin to the animals’ food also had the “highly disconcerting effect” of inducing cholestasis, leading to HCC in mice that were kept on the diet for six months.

Mice that were prone to HCC exhibited gut altered gut microbiota, or dysbiosis, characterized by increased fiber-fermenting bacteria and proteobatceria, and this suggested a link between inulin, bacterial fermentation, and HCC. The possibility of an association was strengthened by the finding that inulin-fed mice that were treated using broad-spectrum antibiotics to reduce gut bacteria didn’t develop HCC. Germ-free mice that completely lacked gut bacteria were also free from liver cancer after being fed an inulin-enriched diet. And when the scientists added dietary beta-acids derived from the hop plant Humulus lupulus, to inhibit fermentation, inulin-fed mice were again spared from developing liver cancer.

“Strikingly, feeding beta-acids to inulin-fed mice averted liver cancer, which further reinforces our hypothesis that gut bacterial dysmetabolism primarily driving liver cancer in these mice,” comments Vishal Singh, Ph.D., a Crohn’s and Colitis Foundation Fellow at the University of Toledo, and co-lead author of their published paper.

Subsequent studies found that the mouse models mice did develop liver cancer when fed on diets to which other soluble fibers (fructooligosaccharide (FOS) and pectin) had been added, but not when their diet included the insoluble fiber cellulose. “Cellulose could not be fermented by gut bacteria present in mice or humans,” comments Beng San Yeoh, co-lead author of the study and a doctoral student at Pennsylvania State University. “This finding again highlights the link between bacterial fermentation of soluble fiber and liver cancer development in these mice.”

Interestingly, a high-fat diet enriched with inulin induced dysbiosis and HCC in normal, wild-type mice. The reported study used inulin derived from the chicory root, which is used to fortify the fiber content of processed foods. “Soluble fibers added to processed foods are not part of a natural meal,” notes Dr. Singh. “The inulin used in this study is from chicory root, which is not a food we would normally eat. In addition, during the extraction and processing of the fiber, it goes through a chemical process. We don’t know how the body responds to these processed fibers.”

The authors say the results indicate that not all fibers are created equal. “Our study is going against the conventional wisdom that fiber is good, no matter how they get it,” Dr. Vijay-Kumar comments. “We do not want to promote that fiber is bad. Rather, we highlight that fortifying processed foods with refined soluble fiber may not be safe or advisable to certain individuals with gut bacterial overgrowth or dysbiosis, whose abnormal fermentation of this fiber could increase the susceptibility to liver cancer.”

“The most intriguing and key finding of this study is the absolute requirement of soluble fiber-feeding to develop HCC,” the authors comment. “It is intriguing to note that our observations on the adverse effects of fermentable fiber is not restricted to inulin alone, but broadly applicable to other types of soluble fibers, including pectin and FOS … Further studies will certainly be needed to disentangle the ‘harmful’ from the ‘beneficial’ aspects of gut fermentation, thus paving the way for personalized use of fermentable fiber to safely promote health.”

The team is advocating that further studies are “urgently needed” to see if processed soluble fibers can promote cholestasis and HCC in humans. “Interestingly, they note, about 50% of adults in the U.S. consume dietary supplements that are claimed to improve health. These supplements generally aim to provide purified versions of the beneficial components of fruits and vegetables. “However, some consumers of these products develop adverse effects, including jaundice and cholestasis following intake of multi-ingredient plant-derived supplements,” the team writes, and the U.S. Drug-Induced Liver Injury Network (DILIN) study, reported in 2014, indicated that plant-derived, purified supplements are “not universally harmless.”

The researchers suggest that their latest work adds weight to this suggestion, with the finding that highly refined fermentable fibers can promote cholestasis and subsequently HCC in mice.  “Such findings should give common pause to the common and increasing incorporation of such fibers into process foods that might contribute to the recently defined association of consumption of ultra-processed foods with the incidence of cancer.”