Excess dietary fructose consumption has a pro-colitic effect that may worsen intestinal inflammation in individuals with inflammatory bowel diseases (IBD), according to findings from a study published in Cellular and Molecular Gastroenterology and Hepatology.1
A high fructose diet (HFrD) was found to increase the severity of experimental colitis in several murine models in a microbiota-dependent manner. The pro-colitic activity observed in mice fed an HFrD “can be explained by changes in the composition, distribution, and metabolic function of resident enteric microbiota,” the investigators said.1
To determine whether an HFrD alters gut luminal microbiota, leading to worsened colitis, Montrose et al treated mice with broad-spectrum antibiotics for 3 weeks. The investigators specifically sought to evaluate whether antibiotic-reduced bacterial abundance would assuage HFrD-mediated spikes in severity of colitis. Treatment with antibiotics translated to an approximate 500-fold reduction in fecal bacterial load per quantitative real-time polymerase chain reaction assessment using a general bacterial primer (Ct value: 16 ± 0.4 vs 25 ± 0.7; P <.001). The mice were subsequently fed a control diet (AIN-93G purified) containing corn starch, maltodextrin, and sucrose in an approximately 60:20:20 ratio as the carbohydrate sources (64 kcal%) or the HFrD for 1 week, followed by 1 week of dextran sodium sulfate (DSS) exposure. The mice continued on the control diet or HFrD during DSS exposure. Control or antibiotic-containing drinking water was given throughout the experimental period.1
Antibiotic treatment was found to prevent HFrD-induced worsening of colitis. However, the HFrD led to more severe colitis than the control diet in mice that did not receive antibiotics. Worsened colitis was also seen in specific pathogen-free mice fed the HFrD; however, this trend was not observed in germ-free mice.1
The investigators subsequently validated the microbial significance of this colitic activity by transferring the colonic content of control diet-fed or HFrD-fed mice to recipient mice that were fed the control diet and challenged with DSS. More severe colitis was seen in mice that received fecal material from HFrD-consuming mice vs mice consuming the control diet. The data “suggest that exacerbation of DSS-induced colitis by HFrD is dependent on gut microbiota,” investigators surmised.1
Importantly, the results, which underscore the clinical link between diet-microbe interactions and intestinal inflammation, may help inform diet decisions in the IBD setting.2
“Our findings provide evidence of a direct link between dietary fructose and IBD and support the concept that high consumption of fructose could worsen disease in people with IBD. This is important because it has the potential to provide guidance on diet choices for IBD patients, something that is currently lacking,” said David C. Montrose, PhD, lead author of the study.2
The incidence of IBD has increased globally over the past half century, and fructose consumption has simultaneously risen by roughly 30% in the United States over the past 3 decades.1 Data from the Centers for Disease Control and Prevention show that approximately 3 million Americans are diagnosed with IBD annually, which represents an approximately 30% increase in incidence from the late 1990s.2
Findings from this investigation complement recent data indicating that an HFrD enhanced DSS-induced colitis in mice and support further study of fructose consumption in relation to pro-colitic activity.1
Prior to assessing the effect of an HFrD on gut luminal microbiota, the investigators examined the clinical implications of an HFrD on the etiopathogenesis of murine colitis in antibiotic-treated and germ-free mice. Wild-type C57BL/6 male mice received 1 of 3 isocaloric diets: the control diet; a high-glucose diet based on the control diet, in which all carbohydrate content came from glucose; and the HFrD, consumed across 2 weeks, in which all carbohydrates came from fructose. The investigators concurrently challenged the mice with low-dose (1%) DSS in drinking water to induce colitis and evaluated colitis severity. Colitis was worse in mice fed an HFrD vs those that consumed the control diet or high-glucose diet. Expression of pro-inflammatory cytokines was also highest in mice fed the HFrD compared with mice that ate the control diet after 7 days of DSS exposure.
The investigators also tested whether feeding mice an amount of fructose comparable to that ingested by “high fructose consumers” within the United States would also exacerbate colitis. In mice fed a diet containing 15 kcal% fructose for 1 week and subsequently challenged with DSS, fructose also led to worsened colitis. By contrast, increased glucose intake did not intensify experimental colitis.1
The significance of the study findings stems partly from the difficulty of identifying a link between high fructose intake and worsened IBD, according to Dr Montrose, an assistant professor and lab head in the Department of Pathology at Stony Brook University School of Medicine in Stony Brook, New York.
“There is anecdotal evidence that consumption of high amounts of sugar, including fructose, worsens IBD symptoms, but it is a hard thing to evaluate in humans. Accurate dietary records are challenging to obtain from patients and would have to be kept for a long period of time to gain knowledge on what foods may or may not impact the occurrence of flares or severity of symptoms. The helpful thing with animal studies is that we can precisely control the diet so we know exactly what the animals are consuming. With all that being said, our work certainly supports a rationale for carrying out focused studies in IBD patients,” Dr Montrose told Gastroenterology Advisor.
The investigators behind this study, including Dr Montrose, will next seek to develop interventions to stymie the pro-inflammatory effects of fructose. They will also study whether an HFrD increases tumorigenesis associated with colitis. This clinical inquiry is critical, because patients with IBD are at increased risk of developing colon cancer due to chronic gut inflammation.2
1. Montrose DC, Nishiguchi R, Basu S, et al. Dietary fructose alters the composition, localization, and metabolism of gut microbiota in association with worsening colitis. Cell Mol Gastroenterol Hepatol. Published online September 19, 2020. doi:10.1016/j.jcmgh.2020.09.008
2. Study reveals dietary fructose heightens inflammatory bowel disease. News release. Stony Brook Medicine; September 29, 2020. Accessed November 19, 2020.