Refined fiber inulin promotes inflammation‐associated colon tumorigenesis by modulating microbial succinate production

Abstract

Background and AimThere is an increased risk of colon cancer associated with inflammatory bowel disease (IBD). Dietary fibers (DFs) naturally present in vegetables and whole grains offer numerous beneficial effects on intestinal health. However, the effects of refined DFs on intestinal health remain unclear. Therefore, we elucidated the impact of the refined DF inulin on colonic inflammation and tumorigenesis.MethodsFour‐week‐old wild‐type (WT) mice were fed diets containing insoluble DF cellulose (control) or refined DF inulin for 4 weeks. A subgroup of mice was then switched to drinking water containing dextran sulfate sodium (DSS, 1.4% wt/vol) for colitis induction. In another subgroup of mice, colitis‐associated colorectal cancer (CRC) was initiated with three 7‐day alternate cycles of DSS following an initial dose of mutagenic substance azoxymethane (AOM; 7.5 mg/kg body weight; i.p.). Post 7 weeks of AOM treatment, mice were euthanized and examined for CRC development.ResultsMice consuming inulin‐containing diet exhibited severe colitis upon DSS administration, as evidenced by more body weight loss, rectal bleeding, and increased colonic inflammation than the DSS‐treated control group. Correspondingly, histological analysis revealed extensive disruption of colon architecture and massive infiltration of immune cells in the inulin‐fed group. We next examined the effect of inulin on CRC development. Surprisingly, significant mortality (~50%) was observed in the inulin‐fed but not in the control group during the DSS cycle. Consequently, the remaining inulin‐fed mice, which completed the study exhibited extensive colon tumorigenesis. Immunohistochemical characterization showed comparatively high expression of the cell proliferation marker Ki67 and activation of the Wnt signaling in tumor sections obtained from the inulin‐fed group. Gut microbiota and metabolite analysis revealed expansion of succinate producers and elevated cecal succinate in inulin‐fed mice. Human colorectal carcinoma cells (HCT116) proliferated more rapidly when supplemented with succinate in an inflamed environment, suggesting that elevated luminal succinate may contribute to tumorigenesis.ConclusionsOur study uncovers that supplementation of diet with refined inulin induces abnormal succinate accumulation in the intestinal lumen, which in part contributes to promoting colon inflammation and tumorigenesis.

Gastrointestinal microbiota-directed nutritional and therapeutic interventions for inflammatory bowel disease: opportunities and challenges

“…Although significant evidence suggests that dietary fibers and their bacterial fermentation products benefit the management of IBD, it is crucial to consider these findings in the context of both healthy and diseased (ongoing intestinal inflammation) states. Emerging data suggest that FDFs such as inulin may worsen symptoms in some patients with IBD [ 38 , 39 , 42 ]. This highlights the need for further research on the specific benefits of different fiber types in IBD.…”

“…This highlights the need for further research on the specific benefits of different fiber types in IBD. Our own work has revealed that the dietary fiber inulin exacerbates intestinal inflammation [ 38 ] and colitis-associated colon tumorigenesis [ 39 ], while structurally distinct fiber pectin offers protection against colitis, emphasizing the potential risks and benefits associated with distinct fiber types [ 38 ]. This observation finds support in other studies as well [ 40 , 41 ].…”

Colorectal cancer and inulin supplementation: the good, the bad, and the unhelpful

“…Despite the promising results shown with inulin supplementation and a general consensus surrounding the benefits of inulin for gut health, more recent studies in mice show that inulin may produce harmful effects. These include an increased production of tumorigenic microbial metabolites, including secondary bile acids [ 91 ] and succinate—a key intermediate metabolite in SCFA production [ 92 ]. Succinate has been shown to promote tumor progression and metastasis through the activation of tumor-associated macrophages and the inhibition of CD8 + T-lymphocyte infiltration into the tumor microenvironment [ 93 , 94 ].…”

“…While inulin has been shown to exacerbate colitis [ 97 , 98 ] and colitis-associated CRC [ 92 ], it has also been linked to non-colitis-associated CRC tumorigenesis [ 99 , 100 ]. At the preclinical stage, inulin has been shown to promote the growth of genotoxin-producing bacteria, induce microbial-mediated immunosuppression, and drive the progression of colonic adenomas towards malignancy [ 99 , 100 ].…”

Deciphering the impacts of gut and tissue microbiome on human cancers

“…In contrast, a research group led by Dr. Vishal Singh observed that refined dietary fiber inulin, commonly present in processed foods, causes abnormal accumulation of succinate in the gut, which leads to colon inflammation and tumorigenesis in a mouse model. 2 They have previously shown that inclusion of inulin-enriched high-fat diet promotes hepatocellular carcinoma in mice. Here, the authors discuss that refined inulin may selectively enrich particular bacterial groups that enhance colonic inflammation.…”